CLASS ROOM DISCUSSION
HEMOLYTIC DISEASE OF NEWBORN (HDN)
MSC 2ND YEAR
CPMS College of Nursing
It is an isoimmunity hemolysis associated with ABO or Rh
incompatibility. Hemolytic disease of the newborn and fetus
(HDN) is a destruction of the red blood cells (RBC) of the
fetus and neonate by antibodies produced by the fetus.
It is a condition in which the life span of the fetal/ neonatal
red cells is shortened due to maternal allo-antibodies against
red cells antigens acquired from the father.
A condition in which fetus or neonate’s red blood cell (RBC) are
destroyed by Immunoglobulin G (IgG) antibodies produced by
"hemolytic" means breaking down of red blood cells
"erythroblastosis" refers to making of immature red blood cells
"fetalis" refers to fetus
Haemolytic disease of the new born (HDN) has been known for
centuries with its typical and poor prognosis. The first described by a
French midwife who delivered twins in 1609.One baby was swollen
and died soon after birth, the other baby developed jaundice and died
several days later. For the next 300 years, many similar cases were
described in which new-borns failed to survive.
During 1970s, the routine antenatal care included screening of all
expectant mothers to find those whose pregnancy may be at risk of
HDN, and giving preventative treatment accordingly. This has led to
decrease cases in the incidence of HDN, particularly severe cases that
were responsible for stillbirth and neonatal death.
The incidence of Rh negative in the European and American whites, is about 25-
17%; it is very much insignificant in China (1%) and almost nil in Japan.
About 60% of Rh-positive men are heterozygous at the D locus.
Overall a Rh-negative woman having the chance of Rh-positive fetus is 60%,
irrespective of the father’s genotype.
In India, the incidence is about 5-10% ( South India—5%, North India—10%)
in hospital statics.
Hemolytic disease of the fetus and newborn (HDFN) affects an estimated 3 in
100,000 to 80 in 100,000 patients annually. Before the establishment of modern
therapy, 1% of all pregnant women developed Rh alloimmunization.
HDN is occurred when a mother with Rh-negative
blood becomes pregnant with Rh-positive baby
that inherited from Rh-positive father.
It occurs when anti-D is stimulated in mother
plasma due to mother’s immune response to the
antigen D on fetal’s red blood cells.
This is due to anti-D is an IgG that capable to cross
placenta and hence delivered to fetal circulation.
Rh caused HDN is less common but more severe.
HDN is arouse when a mother with blood type O
becomes pregnant with a fetus with different blood types
A, B or AB.
ABO antibodies is natural occurring antibodies that
ABO caused HDN is commonly occur but less severe
Others unexpected immune antibody (other than anti-D)
Other Rh antibodies:
anti-E (second most common, mild disease)
anti–c (third most common, mild to severe)
anti-C and anti-e (rare)
antibody combination (anti-c and anti-E occurring together, can be severe)
• Infection: bacterial, viral, parasitic
• Vitamin E Deficiency
Kell system antibodies (uncommon causes)
Duffy, MNSs and Kidd system antibodies (rare causes)
*The Kell antigen system(also known as Kell–Cellano system) is a
group of antigens on the human red blood cell surface which are
important determinants of blood type and are targets
for autoimmune or alloimmune diseases which destroy red blood cells.
Kell can be noted as K, k, or Kp
Duffy antigen/chemokine receptor (DARC) also known
as Fyglycoprotein(FY) or CD234 (Cluster of Differentiation 234)
is a protein that in humans is encoded by the DARC gene.
The Duffy antigen is located on the surface of red blood cells, and
is named after the patient in which it was discovered. The protein
encoded by this gene is a glycosylated membrane protein and a
non-specific receipt or for several chemokines. The protein is also
the receptor for the human malarial parasites Plasmodium
vivax and Plasmodium knowlesi. Polymorphisms in this gene are
the basis of the Duffy blood group system.
• In a first pregnancy, Rh sensitization is not likely. Usually it only
becomes a problem in a future pregnancy with another Rh positive
• When the next pregnancy occur, the mother's antibodies cross the
placenta then reacts with an RBC antigen to fight the Rh positive
cells in the baby's body that the baby has inherited from the father,
and that is foreign to the mother.
• Hence, the antigen antibody interaction occurs.
• Sensitization of baby’s red blood cell (RBC) by mother’s IgG
antibody causes the baby’s RBC to be destroyed.
• These antibody-coated RBCs are removed from fetal
circulation by the macrophages of the spleen and liver.
• The severity of anemia depends on the amount of mother’s
antibody, its specificity, its avidity, and others characteristics.
• Anemia will stimulate bone marrow to produce more RBC
including immature RBC, which is then released to fetus
circulation. This is also known as erythroblastosis fetalis.
ABO INCOMPATIBILITY OF HDN
• ABO HDN is due to incompatibility of ABO between mother and fetus.
• A portion of the mother’s ABO antibodies may be IgG and cross the
• It thus sensitizes the fetal cells.
• This condition can occur on the first pregnancy and can occur without there
having been transfusion.
• The mechanism of ABO HDN is similar to the RH HDN.
• Occurrence of ABO HDN is somewhat common, but fortunately it is not
often very severe.
SEROLOGICAL EFFECT OF HEMOLYTIC
DISEASE IN NEWBORN (HDN)
Depending upon the degree of agglutination and destruction of the fetal
red cells, various types of hemolytic disease appears.
• Once antigen-antibody interaction occurs, antibody-coated red blood
cells are removed from fetal circulation by macrophages of the
spleen and liver which lead to anemia
• Anemia limits the ability of the blood to carry oxygen to the baby's
organs and tissues.
• In response to anemia, fetal bone marrow and other hematopoietic tissues in
the spleen and liver increase the amount of red blood cells production.
• Baby's responds to the hemolysis by trying to make more red blood cells
very quickly in the bone marrow and the liver and spleen.
• Organs enlarge - hepatosplenomegaly.
• New red blood cells released prematurely from bone marrow and are
unable to do the work of mature red blood cells produced many nucleated
red blood cell which is unable to carry oxygen.
• As the red blood cells break down, bilirubin is formed
• Accumulation of bilirubin in body tissue and fluid results in
• Due to immature liver of the newborn and inability to conjugated
the unconjugated bilirubin result in the unconjugated bilirubin
increasing and crossing the blood brain barrier and cause
• Kernicterus or bilirubin encephalopathy results from high
levels of unconjugated bilirubin in the fetus blood which is
more than 20 mg/dL.
• Because unconjugated bilirubin are lipid soluble and toxic, it
can crosses the blood-brain barrier and it will penetrates
neuronal and glial membrane thus cause neurotoxicity
• Patients surviving kernicterus have
severe permanent neurologic symptoms
such as :
c) Muscular rigidity
f) Mental retardation
As the fetus ‘s anemia worsen, the fetus
accelerates red cells production
It is most serious form of Rh hemolytic
disease. Excessive destruction of the
fetal red blood cells leads to severe
anemia, tissue anoxemia and metabolic
Liver and spleen increase in size due to
increase production of red blood cells.
As a result, portal hypertension occur, causing the liver to reduces its
As a result of fetal anoxemia, there is damage to the liver leading to
hypoproteinemia which is responsible for generalized edema ( hydrops
fetalis), ascites and hydrothorax.
Fetal death occurs sooner or later due to cardiac failure.
The baby is either stillborn or macerated and even if born alive, dies
DIAGNOSTIC FEATURES OF HYDROPS FETALIS
Mother is Rh-negative.
Serological examination reveals presence of Rh- antibody.
There may be presence of polyhydramnious.
Previous history of affection of a baby due to hemolytic disease.
Sonography: ( Real time combined with pulse Doppler) to detect
edema in the skin, scalp and pleural or pericardial effusion and
Straight X-ray abdomen showing: “Buddha” position of the fetus with
halo around the head.
• Varies from mild jaundice and anemia to hydropsfetalis(with ascites,
pleural and pericardial effusions)
• Chief risk to the fetus is anemia.
• Extramedullary hematopoiesis due to anemia results in
Risks during labor and delivery include:
• Asphyxia and splenic rupture.
Postnatal problems include:
• Pulmonary hypertension
• Pallor (due to anemia)
• Edema (hydrops, due to low serum albumin)
• Respiratory distress
• Coagulopathies (↓ platelets & clotting factors)
• Kernicterus (from hyperbilirubinemia)
Hypoglycemia (due to hyperinsulinemnia from islet cell hyperplasia
ANTENATAL INVESTIGATION PROTOCOL OF RH- NEGATIVE
Investigation of blood for Rh and ABO grouping becomes almost a routine
during the first antenatal visit in first trimester.
If the woman is found Rh-negative, Rh grouping of the husband is to be done to
find out whether the pregnancy is a result of incompatible or compatible
If the husband is found to be Rh positive, further investigation are to be carried
out which aims at:
I. To detect whether the woman has already been immunized to Rh antigen;
II.To forecast the likely affection of the baby
III.To anticipate and formulate the line of management of a likely affected baby
If the woman is a primigravida with no previous history of blood
transfusion, it is quite unlikely that the baby will be affected.
In a parous woman, a detail obstetric history has to be taken. The
classic history of fetal affection in the form of stillbirth or neonatal
death due to severe jaundice following one or two uneventful birth
is quite suggestive. History of prophylactic administration of anti-D
immunoglobulin following abortion or delivery should be enquired.
In all cases of Rh-negative women irrespective of blood grouping and parity, IgG
antibody is detected by Indirect Coombs’ test’
If the test is found negative at 12th week, it is to be repeated at 28th and 36th week in
primigravida. In multigravida, the test is to be repeated at monthly intervals from 24
If test is found positive: The patient should be supervised in centers equipped to tackle
with Rh problem ( specialized fetal medicine unit).
Genotype of the husband is to be determined. If he is found to be homozygous, the fetus
is likely to be affected and in heterozygous, the fetus may be affected in 50% cases. In
that case fetal blood group is determined. If the fetus is found to be Rh(D) negative, no
further tests are required and routine care is continued.
The diagnosis of alloimmunization can be made early in the pregnancy
by chorionic villus sampling to determine fetal blood grouping and type.
The drawback to the procedure include possible early spontaneous
abortion and the risk of fetomaternal hemorrhage and alloimmunization.
Another diagnostic method to determine alloimmunization is an
Amniocentesis using polymerasechain reaction (PCR) to determine the
fetal blood type, hemoglobin, hematocrit and presence of maternal
Percutaneous umbilical fetal blood sampling( PUBS) is considered to be
most accurate means for assessing the severity of fetal hemolytic disease
in the absence of fetal hydrops.
Ultrasonography is considered an important adjunct in the
direction of alloimmunization; Ultrasonography may also be used
to detect fetal anemia in the non hydroptic fetus.
• A needle is introduced through abdomen and uterus and into the
amniotic sacs. A small amount of amniotic fluid is remove for
• Liley’s graph is use to evaluate the level of bile pigment in the
amniotic fluid to measure hemolysis in the fetus.
• Positive maternal antenatal antibody findings and/or diagnosis of anemia or
• Positive neonatal direct Coombs test
• Hemolysis on blood film findings
• CBC results show Anemia
• Hypokalemia, hyperkalemia and hypocalcemia are common after exchange
Rh Immune Globulin (RhIG or Rhogam)
Alloimmunization in pregnant woman can be prevented by
administration of Rh immune globulin (RhIG or Rhogam).
RhIG is a concentrate of IgG anti-D prepared from pooled human
plasma of D-negative people who have been exposed to the D antigen
and who have made antibodies to it.
Anti-D products contain specified levels of anti D and are
available for intramuscular or intravenous administration.
Significance of administration of RhIG
(i) RhIG prevents alloimmunization in D-negative mother exposed
to D-positive fetal red cells. In the meantime, it protects mother from
being sensitized to D antigen of fetal during pregnancy and after
delivery of infant.
(ii) RhI Gsuppresses mother’s immune response following exposure
to D-positive fetal red cells.
(iii) RhIG prevents the mother from producing anti-D.
(iv) RhIG protects subsequent D-positive pregnancies but must be
given each time the woman is pregnant with D-positive fetus.
RhIG is given by injection into mother’s muscle (intramuscular).
Giving RhIG to D-negative pregnant woman prevents her immune
system from producing its own anti-D (which would attack her D-
positive fetal red cells).
When RhIG is introduced into D-negative mothers’s bloodstream,
RhIG antibodies will locate D-positive fetal red cells.
RhIG antibodies will attach to D-positive fetal red cells and covering
their presence from mother’s immune system.
Therefore, sensitization of anti-D to D-positive fetal red cells can be
GUIDELINES FOR RHIG ADMINISTRATION IN D-
NEGATIVE PREGNANT WOMAN :
(i) All doses should be given within 72 hours of delivery or
procedure. If she is not given RhIG within 72 hours after the birth
of an Rh-positive baby, she will begin to make antibodies to the
fetal blood cells.
(ii) Woman should not be sensitized to D antigen.
iii) 50 µg dose - Up to 12th week of gestation for abortion,
miscarriage and end period of ectopic pregnancy.
(iv) 120 µg dose
- End period of pregnancy which is after 12th week of gestation.
- After amniocentesis.
- After delivery of D-positive infant.
(v) 300 µg dose
- At 28th week of gestation
- After amniocentesis
- After delivery of D-positive infant.
INTRAUTERINE TRANSFUSION (IUT)
• Red Blood Cells (RBCs) are infused into
abdominal cavity of fetus and then
absorbed into fetal circulation to avoid
hydrops fetalis and fetal death.
• Can be done as early as 17 weeks.
• In intraperitoneal IUT, a needle is passed
through the mother’s abdomen and into
the abdomen of the fetus by the help of
ultrasound image to determine the
position of the fetus and placenta.
Selection of Blood for IUT:
Most IUTs are accomplished using group O.
Rh-negative RBCs that are less than 7 days from collection
Ctyomegalovirus (CMV) antibody negative
Hemoglobin S negative
Fresh blood is used to provide RBCs with longest viability and to
avoid lower pH, decreased 2,3-diphospoglycerate, and elevated
RBCs are usually dry packed to remove residual anti-A and
anti-B and reconstituted with group AB fresh frozen plasma to
provide coagulation factors.
• The risk of these procedures is now largely dependent on the
prior condition of the fetus and the gestational age at which
transfusion is commenced.
• Titer greater than 32 for anti-D and 8 for anti-K OR four fold
increase in titer indicates need for analysis of amniotic fluid.
• Perform at 28 weeks if HDN in previous child
• Perform at 22 weeks if previous child severely affected
• Perform if maternal antibody increases before 34th wk.
• High values of bilirubin in amniotic fluid analyses by the
Liley method or a hemoglobin concentration of cord blood
below 10.0 g/mL.
• Phototherapy is the treatment of
• Phototherapy accelerates bilirubin
metabolism through the process of
• The effective wavelength of light(
blue or blue- green light) seems to
be in the 420- to 475 nm range.
• During photoisomerization or photooxidation, the insoluble
form of unconjugated bilirubin is converted into water soluble
form which permits more rapid excretion without conjugation,
through the bile or urine.
• However phototherapy may not be effective in controlling
hyperbilirubinemia secondary to HDN if the concentration of
bilirubin rises at rate of 0.5 to 2.0 mg/dl per hour.
• In the cases, exchange transfusion must occur.
Exchange transfusion is a life-saving
procedure in severely affected hemolytic
disease of the newborn (HDEN). With the
advent of wider use of prophylactic anti-D
immunoglobulin, less and less problem
babies are born and through exchange
transfusion, the incidence of kernicterus
has also been reduced.
Rh-positive with Direct Coombs’ test positive babies
Cord blood bilirubin level > 4mg/dl and hemoglobin is <
Rising rate of bilirubin is over 1mg/dl/hour despite
Total bilirubin level 20mg/dl or more.
To stop hemolysis, and bilirubin production and prevent
To correct anemia and to improve congestive cardiac failure of
To provide compatible red blood cells adequate oxygen
To eliminate the circulatory bilirubin.
To decrease the level of incompatible antibody in the baby.
While about 80-90% of the fetal blood is exchanged during the procedure,
transfusion of Rh-negative blood cannot alter the Rh- factor of the baby’s
blood. The replacement temporarily helps to tide over the crisis from
anemia and hyperbilirubinemia for about two weeks. Therefore, the baby
is quite capable to get rid of the maternal antibodies by producing
sufficiently his own Rh-positive blood.
• Full-term infants rarely require an exchange transfusion if the infant
undergo the phototherapy.
• The exchange transfusion is done if the total bilirubin level is approaching
20mg/dL and continues to rise despite the baby undergo the phototherapy.
The blood for exchange should be Rh-negative, whole blood with the same
blood ABO grouping to that of the baby ,otherwise ‘O’ negative packed
RBCs cross-matched against the mother and type-specific fresh frozen
plasma ( <7days old).
• The amount is about 160ml/kg body weight of the baby.
*In an older child or adult, normal values of direct (conjugated) bilirubin
are from 0 to 0.3 milligrams per deciliter (mg/dL). Normal values of total
bilirubin (direct and indirect) are from 0.3 to 1.9 mg/dL.
In a newborn, higher bilirubin is normal due to the stress of birth. Normal
bilirubin in a newborn would be under 5 mg/dL, but up to 60 percent of
newborns have some kind of jaundice and bilirubin levels above 5 mg/dL.
• The procedure is best to be carried out under a
servo control radiant warmer.
• The route of transfusion should be preferably be
through umbilical vein.
• A plastic catheter of 1mm diameter is passed
about 7cm beyond the umbilicus so as to place
it in the inferior vena cava.
• In late transfusion, femoral route through
saphenous vein is the choice. Entire set should
be air tight and to be periodically flushed with
heparinized saline (1000 unit in 100ml) to
• 30 min before the exchange transfusion, give albumin 1g/kg to
increase the bilirubin bound to albumin in the circulation and make the
exchange transfusion more effective.
• Blood should be warmed to 370 C
• 15 ml of fetal blood is withdrawn first followed by 10 ml to be pushed
in- return slowly ( push- pull method), taking at least 1 minute.
• For every 100ml of blood transfused, one milli equivalent sodium
bicarbonate is given to combat metabolic acidosis and 1 ml of 10%
calcium gluconate to prevent tetany due to transfusion of citrated
• Exchange 2 times the blood volume, at 85mL/kg, by using the
isovolumic technique. This technique done by withdrawing blood from
upper atrium canal and infusing through upper ventricle canal(low
right atrium with tip intra ventricle canal).
• Do not infuse blood through upper ventricle canal if tips is in portal
• The blood should be warmed and the bag agitated every few minutes
to prevent settling of the RBCs.
• The procedure should be supervised by an expert team work.
POST TRANSFUSION CARE
1. The baby is placed under a radiant warmer
2. Keep the newborn NPO for 2-4 hours before exchange to prevent aspiration.
3. The umbilicus is to be inspected frequently for any evidence of bleeding.
4. Check vital signs frequently.
5. Serum bilirubin is to be estimated 4 hours after transfusion and to be repeated as
required. Occasionally, the level of conjugated bilirubin may remain higher and
phototherapy should be continued
6. Hypoglycemia (due to increased insulin secretion) is to be checked by blood
glucose estimation by blood glucose estimation post transfusion 4 hourly.
• It is widely used treatment of immune-mediated disease.
• This treatment is applied to the pregnant women with high antibody titer, or
that has past history of stillbirth due to HDN.
• This procedure are effective in decreasing the antibody titer and quantity of
• Plasma exchange can reduce antibody titer up to 75%.
• Beside that, it also use for a way to delay the need for fetal intervention that
has been hydropsfetalis (edema) in which before 22 week gestation in a
INTRAVENOUS IMMUNE GLOBULIN
• Intravenous immune globulin (IVIG) is made up from plasma isolated
• This treatment use strengthen body immune system beside to treat immune
• Intravenous Immunoglobulins were found to decrease hemolysis leading to
reduction in serum bilirubin level.
The immunoglobulin could act by occupying the FC receptors of reticulo-
endothelial cells preventing them from taking up and lysing antibody coated
RBCs. This subsequently leads to decrease in the need for exchange
MANAGEMENT OFABO IBCOMPATIBILITY
The treatment of ABO hemolytic disease is early detection and implementation of
phototherapy for the reduction of hyperbilirubinemia.
The initial diagnosis is often more difficult because the reduction of
hyperbilirubinemia. The initial diagnosis is often more difficult because the direct
coombs’ test may negative or weekly reactive.
The presence of jaundice within the 24 hours elevated serum bilirubin level, RBC
spherocytosis, and increased erythrocyte production are diagnostic of ABO
In some centers IV immune globulin transfusion are used in combination with
phototherapy to treat ABO incompatibility.
Exchange transfusion is not commonly required for ABO incompatibility except
when phototherapy fails to decrease bilirubin concentration.
PLAN FOR DELIVERY
Unimmunized mothers: In cases where there is no detectable antibody
found during pregnancy, an expectant attitude is followed till term.
Tendency of pregnancy to overrun the expected date should not be
Immunized mothers: Whenever there is evidence of hemolytic process in
the fetus in utero, the patient should be shifted to an equipped center
specialized to deal with Rh problems. An intensive neonatal care unit,
arrangement for exchange transfusion and an expert neonatologist are
the basic requirements to tackle the affected babies.
METHODS OF DELIVERY
1.Amniotomy ( low rupture of membranes) is quite effective, if
termination is done near term. Vaginal prostaglandin gel
(PGE2) could be used to make the cervix ripe.
Cesarean section: In cases when termination has to be done
prematurely ( like 34-37 weeks), the cervix will be
unfavorable and considering the severity of affection and
urgency of termination, cesarean section is a safe procedure
CARE DURING DELIVERY
(i) Careful fetal monitoring is to be done to detect at the earliest,
evidences of distress;
(ii) prophylactic ergometrine during second stage should be withheld;
(iii) gentle handling of the uterus in the third stage and
(iv) to take care of post-partum hemorrhage.
Cesarean section: (i) To avoid spillage of blood into the peritoneal cavity and
(ii) routine manual removal of placenta should be withheld.
Clamping the umbilical cord: In either methods, the cord is to be clamped as
quickly as possible to minimize even minute amount of antibody to cross to the fetus
from the mother. The cord should be kept long (15-20cm) for exchange transfusion, if
Collection of cord blood for investigation: Cord blood sample is to be taken from
the placental end of the cut cord. The cord should not be squeezed to prevent
contamination with Wharton's jelly. About 5 mL of blood(2 mL oxalated and 3 mL
clotted) should be collected for the following tests:
Clotted blood: ABO and Rh grouping, reticulocyte count, direct Coombs' test and
Oxalated blood: Hemoglobin estimation and blood smear for presence of immature
Hemolytic disease of newborn occurs when IgG antibodies produced by the
mother against the corresponding antigen which is absent in her, crosses the
placenta and destroy the red blood cells of the fetus. Proper early
management of Rh- HDN saves lives of a child and future pregnancies.
ABO- HDN is usually mild. Other blood group antigens can also cause
The diagnosis, acute management, and follow‐up of neonates with HDN
still represent an important area of activity for maternity/neonatal services.
Through the highly successful use of prophylactic Rh D immunoglobulin in
Rh D negative women, Rh D allo‐immunisation and its sequelae have
greatly diminished. As a result, ABO incompatibility is now the single
largest cause of HDN in the western world. However, with increasing
knowledge at the molecular level, and closer liaison between neonatal
paediatricians and haematologists, the diagnosis of non‐immune causes of
HDN is increasing. As these conditions have an inherited basis and
therefore have implications for other family members (or future children), it
must remain a high priority for all neonatal paediatricians to achieve an
accurate diagnosis in all cases of HDN, and emphasises the point that
patients with persistent neonatal haemolysis should always be fully
investigated and followed up appropriately.
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