Hemolytic Disease of the Fetus

/Newborn

Dr. Dhammika Senevirathne

Consultant transfusion Physician
National Blood Transfusion service
Haemolytic Disease of Newborn
 Hemolytic disease of Fetus/newborn

Hemolytic disease of the new born and fetus

(HDN) is a destruction of the red blood cells
(RBCs) of the fetus and neonate by antibodies
produced by the mother

It is a condition in which the life span of the

fetal/neonatal red cells is shortened due to
maternal allo-antibodies against red cell
antigens acquired from the father
 Aetiology of HDFN
• Maternal antibodies cross the placenta and
bind to the corresponding antigen on fetal red
blood cells.
• Positive DAT with RBC of the newborn infant
cannot be established the diagnosis of HDN
• Evidence of increased red cell destruction also
required to the diagnosis.
• Every newborn infants shows :
 Rising bilirubin levels during first 2-3 days of life
 Fall in HB during the first week of life
Decision ?
 Clinical signs of HDN
• Jaundice – Though this may have a non
immunological cause
• Anemia – ( Excessive fall in Hb levels )
• Enlargement of liver and spleen
Severity of the disease range from Mild
anemia to still birth.
 Depends on number of fetal RBC destroyed
by maternal antibodies and the ability of the
fetus to compensate by an production of new
red cells.( Related to the age of the fetus )
 Origin of the maternal antibodies
• Previous Transfusion
• Stimulation by previous pregnancies.
woman produced IgG 37°C reactive immune
antibodies
Causes
 Common causes for HDN
Rh system antibodies
ABO system antibodies

 Uncommon causes
Kell system antibodies

Rare causes
Duffy system antibodies
MNS and s system antibodies

No occurrence in HDN

Lewis system antibodies
P system antibodies
 Biochemistry of antibodies
IgG1 IgG2 IgG3 IgA IgM IgE
Compliment ++ + +++ - +++ -
fixation

Placental ++ + + - - -
transfer

Lymphocyte / + - + - - -
macrophage
FcR binding
Transfer of Antibody from mother to fetus
• Via the placenta.
• Only blood group reactive IgG antibodies capable of
placenta transfer.
• IgG 1 and IgG 3 due to placental transfer factor which
is locate on the Fc portion of the molecule.
• At delivery; The concentration of IgG tends to be
higher in the infants serum/or plasma than in the
mother's circulation. So Igg is transferred more
readily from mother to the fetus and remain in
23days in infants circulation.
 Disease mechanism - HDN
• There is destruction of the RBCs of the fetus
by antibodies produced by mother

• If the fetal red cells contains the corresponding antigen,

then binding of antibody will occur to red cells

• Coated RBCs are removed by mononuclear

phagocytic system
(Liver and Spleen)
 Causes of feto maternal heamorrhage
 Abortion – therapeutic interventions or evacuation in 1st
trimester
 2nd trimester abortion.
 Ectopic pregnancy
 Chorionic villous sampling.
 Amniocentesis
 Chordocentesis.
 External cephalic version
 Antepartum heamorrhage
 Blunt trauma to abdomen
 Delivery/still birth
 Manual removal of placenta
 FMH – Mixing of fetal blood into
maternal circulation
• 90%- at delivery
• 10%- during pregnancy
• Mostly after 28/52
• FMH not always associated with bleeding PV
• Bleeding PV not always associated with FMH
 Estimation of FMH
• Important in determination of amount of
Anti-D Ig.
 Acid Elution Test ( Kleihauer Test )
 Rosette test
 Flow cytometer
Kleihauer–Betke ("KB")
 Neonatal
liver is immature and
unable to handle
bilirubin

Unconjugated
bilirubin
Conjugated
bilirubin

Coated red blood cell

are hemolysed in
spleen
Pathogenesis; before
birth
Pathogenesis; after
delivery
 Clinical features
• Less severe form
– Mild anemia

• Severe forms
– Icterus gravis neonatorum (Kernicterus)
• Intrauterine death
– Hydrops fetalis
• Oedematous, ascites, bulky swollen & friable placenta
• Pathophysiology
– Extravascular hemolysis with extramedullary erythropoiesis
– Hepatic and cardiac failure
 Hemolytic disease of newborn HDN
BEFORE BIRTH
• Anemia (destruction of red cells)
• Heart failure
• Fetal death (Hydrops fetalis)

AFTER BIRTH
• Anemia (destruction of red cells)
• Heart failure
• Build up of bilirubin
• Kernicterus
• Severe growth retardation
 Rh HEMOLYTIC DISEASE OF NEWBORN
• Antibodies against
• Anti-D and less commonly anti-c, anti-E
• Mother is the case of anti-D is Rh -ve (negative)
• First born infant is usually unaffected
• Sensitization of mother occurs
• During gestation
• At the time of birth
• All subsequent offspring inheriting D-antigen will be
affected in case of anti-D HDN
 Pathogenesis

Fetomaternal Hemorrhage

Maternal Antibodies formed against Paternally derived

antigens

During subsequent pregnancy, placental passage of

maternal IgG antibodies

Maternal antibody attaches to fetal red blood cells

Fetal red blood cell hemolysis

 Laboratory Testing for the
prevention of HDFN
• Identify pregnancies at risk of fetal and
neonatal HDFN
• Identify D negative women may need anti D
immunoglobulin prophylaxis
• Provide antigen negative blood swiftly for
obstetric emergencies.
 Diagnosis and Management
• History; including H/O previous pregnancies or and
disease needing blood transfusion
• At the tme of booking visit all AN mothers tested for
ABO and Rh D testing and ABS
• To detect clinically significant IgG Ab which reacts
at 370C
• Repeat testing required at 28 weeks if first test
negative
• Antibody specificity
• Parental phenotype
• Antibody titers – Dilution method
 32 consider as clinically significant
 Rising titer

• Amniocentesis and cordocentesis

• Concentration of bilirubin
• Spectrophotometric scan
– Indirect method
» Increasing or un-change OD as
Percutaneous
pregnancy advance shows
Umbilical blood
worsening of the fetal hemolytic
sampling
disease
• Fetal blood sample can be taken and
tested for
– Hb, HCT, blood type and DAT
 Diagnosis and Management contd.
• Intrauterine transfusion
– Zone II or III in Lilieys chart
– Cordocentesis blood sample Hb less than 10g/dl
– Ultrasound evidence of hydrops
• Early delivery
• Phototherapy
• Newborn transfusion
• Exchange transfusion
• Effects of transfusion
– Removal of bilirubin
– Removal of sensitized RBCs, and antibodies
– Suppression of incompatible erythropoiesis
– Replace with compatible red cells
Phototherapy

• Nonpolar bilirubin is
converted into 2 types of
water-soluble
photoisomers as a result
of phototherapy
• Decrease in bilirubin is
mainly the result of
excretion of these
photoproducts in bile
and removal via stool
 Diagnosis and Management contd.
• Selection of blood
– Group O RBC’s
– Rh-negative units for Rh-
negative case
– Blood less than 5 days
old
– In CPDA1 anticoagulant
 Selection of Blood for Exchange Transfusion
• Red cells compatible with
maternal and neonatal blood
group
• HCT – 0.5 – 0.6
• Not older than 5 days old - to
reduce risk of hyperkalemia and
for good post transfusion red cell
survival.
• Leucodepleted to prevent CMV
• Not from directed donation.
• Screen for Sickle cell Hb
• Volume
• Term baby – 160 ml/ kg
• Preterm baby – 200 ml/ kg
• Add 60 ml of FFP to packed RBC
in CPDA1(avoid red cells in
additive solution, if not available
centrifuge and remove plasma,
then add FFP
 Selection of Blood for Exchange Transfusion
Mother’s Baby’s Group Red cells Plasma
Group
O Only O O ,A ,B ,AB
O A A ,AB
B B ,AB
AB AB
O O O ,A ,B,AB
A A A (O) A ,AB
B O B ,AB
AB A (O) AB
O O O ,A ,B ,AB
B A O A
B B(O) B
AB B(O) AB
O O O ,A ,B ,AB
AB A A ,O A
B B ,O B
AB AB AB
 Benefits of Exchange Transfusion
• Remove bilirubin
• Remove
antibodies
• Remove antibody
coated RBC
• Replace with
compatible RBC
• Correct anaemia
Potential complications of exchange
transfusion
– Cardiac - Arrhythmia, volume overload, congestive
failure, and arrest
– Hematologic - neutropenia, thrombocytopenia, and
graft versus host disease
– Infectious - Bacterial, viral (CMV, HIV, hepatitis), and
malarial
– Metabolic - Acidosis, hypocalcemia, hypoglycemia,
hyperkalemia,
– Vascular - Embolization, thrombosis, necrotizing
enterocolitis, and perforation of umbilical vessel
– Systemic - Hypothermia
 Anti D Immunoprophylaxis
• Anti D immunoglobulin should be given within 72
hours after any sensitizing event.
• Standard dose 500 IU/1500IU –IM.
• Sensitizing event <20/52 – 250 IU.
• Sensitizing events >20/52 – 500IU.
• Anti D Ig not indicated – already sensitized mother
and mother who has delivered a Rh negative baby.
• If unable to give within 72 h try to give within 10
days.
• 100 IU of IM anti D can suppress sensitization by 1ml
of Rh D positive cells.
 Anti D Prophylaxis
• At 28/52 anti D should be given to mothers
who have negative antibody screening.
• Cord DAT may remain positive due to this
passive anti D
• It is important to know the date when passive
anti D has been before testing
 Passive and Immune anti D
• Passive
• May be present for 6-8 weeks
• Detectable by IAT
• Level may decrease
• Immune
• Continues to be present
• Level may increase
• Detectable by IAT- strongly
 Prevention of Rh- HDN
• Rh Immune Globulin
 Administered antibodies will
bind the fetal Rh- positive
cells
 Spleen captured these cells
by Fc-receptors
 Suppressor T cell response
is stimulated
 Spleen remove anti-D
coated red cells prior to
contact with antigen
presenting cells “antigen
deviation”
 ABO incompatibility
• ABO incompatibility is limited to type O
mothers with fetuses who have type A or
B blood

• in type O mothers, the antibodies are

predominantly IgG in nature
 ABO incompatibility
Less severe : Why ?
• Because A and B antigens are widely expressed in a
variety of tissues besides RBCs, only small portion of
antibodies crossing the placenta is available to bind to
fetal RBCs. In addition, fetal RBCs appear to have less
surface expression of A or B antigen, resulting in few
reactive sites—hence the low incidence of significant
hemolysis in affected neonates.
 ABO HDN contd.
• Signs and symptoms
• Anemia is most of the time mild
• ABO- HDN may be seen in the first pregnancy

• Laboratory findings
• Differ from Rh- HDN; microspherocytes are characteristic of ABO- HDN
• Bilirubin peak is later; 1- 3 days after birth
• Collection of cord blood and testing eluates form red cells will reveal
anti-A or anti-B
• Treatment
• Group O donor blood for exchange transfusion which is rarely required
• Phototherapy
 HDN- due to other antibodies
• Anti-c
• Usually less severe than that cause by Anti-D

• Anti-K
• May cause severe fetal anemia

– Blood transfusion for the treatment should lack

the appropriate antigen
 HDN should be considered in the fetus or neonate
where there is one or more of the following:

• rapidly developing or severe

hyperbilirubinaemia not predicted by maternal
antenatal antibody screening;
• positive maternal antenatal antibody screening
and/or diagnosis of a severely
anaemic/hydropic fetus;
• a positive direct anti‐globulin test (DAT);
• haemolysis detected on blood film
examination;
• prolonged hyperbilirubinaemia.
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