Rhesus isoimmunisation (1)

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Rhesus Isoimmunization

• 14th February, 2023

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Learning Objectives

• At the end of the session a medical student is
  expected to
• Understand the meaning of Rhesus Isoimmunization
• Explain the Pathophysiology / pathogenesis
• List Maternal and Fetal Complications
• List the investigations conducted
• Know how and when to manage a patient with Rhesus
  isoimmunization
• Know prevention of Rhesus isoimmunization

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Introduction

• Antigen D was first discovered in Rhesus monkeys
  by Landsteiner and Weiner in 1940.
• Presence of Antigen D Rhesus positive (Rh)
• 65 of Rh men are heterozygous (Dd) and 35 are
  homozygous (dd).
• The D gene is dominant therefore DD and Dd are
  considered Rh and dd Rh-
• Genetic Locus for Rh antigen is in short arm of
  Chromosome 1

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Rhesus isoimmunization (Red Cell
Alloimmunization)

• Definition
• Production of immune Antibodies in an individual
  in response to a foreign red cell Antigen derived
  from another individual of the same specie
  provided the first one lacks antigens.
• Occurs in two stages
• Sensitization Immunization
• There are 2 methods Mismatched Blood Transfusion
  and Pregnancy.

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A TRANSFUSION OF MISMATCHED BLOOD

• In ABO group incompatibility, there are naturally
  occurring anti-A and anti-B isoagglutinins, which
  result in immediate adverse reaction.
• In Rh group, lacks naturally occurring antibody
  and as such there is no immediate reaction, but
  the red cells carrying the Rh antigen sensitize
  the immunologically competent cells in the body,
  provided the amount is sufficiently large. This
  takes at least 1 week.
• Following a subsequent exposure to the antigen,
  the cells are stimulated to produce more specific
  anti-D antibodies. The women may suffer a severe
  hemolytic reaction to the subsequent mismatched
  transfusion.

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B PREGNANCY (Rh- mother with Rh fetus)

• Fetal Rh antigen can enter maternal blood in
  conditions like
• Abortion/ectopic pregnancy
• Amniocentesis
• Chorionic Villus Sampling (CVS)
• Ante Partum Hemorrhage (PP and AP)
• External Cephalic Version
• During third stage of labour
• Following Caesarean Section
• Manual removal of the placenta
• Abdominal trauma

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PREGNANCY (Rh- mother with Rh fetus)

• 0.1ml is considered as the critical volume of
  fetal blood entering maternal circulation for
  immunization to occur
• Normally Fetal Rh antigens are present by 38th
  day after conception.

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• C. Inadequate dose / improper use of Ig on
  previous occasions

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Antibody formation in the mother

• In ABO isoimmunization (mother and fetus have the
  same ABO group or when the fetus is group O),
  Rh fetal RBCs enter the mothers blood, remain
  in the circulation for their remaining lifespan.
  Removed by RES and are broken down with
  liberation of the Antigen. Antibody production is
  related to the amount of Rh antigen liberated.
  Process takes awhile immunization in a first
  pregnancy is unlikely.
• Detectable Antibody usually develop gt 6 months
  following larger volume of feto-maternal bleed.
  If the feto-maternal bleed lt 0.1 mL, the
  Antibodies may not be detected until boosted by
  further Rh stimulus. Antibodies once formed
  remain throughout life.

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TYPES OF ANTIBODIES FORMED

• IgM First to appear in the maternal circulation
  and agglutinates red cells containing D when
  suspended in saline. This is larger, cannot pass
  through the placental barrier and is not harmful
  to the fetus.
• IgG (incomplete or blocking antibody) It will
  agglutinate the red cells containing D only when
  suspended in 20 albumin. This is smaller, can
  cross the placental barrier and cause damage to
  the fetus.

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Fetal affection by Rh antibody

• The antibody formed in the maternal system (IgG)
  crosses the placental barrier and enters into the
  foetal circulation.
• If the foetus is Rh-positive the antibody becomes
  attached to the antigen sites on the surface of
  the foetal erythrocytes.
• The affected cells are rapidly removed from the
  circulation by the reticulo-endothelial system
  (RES)

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• Depending upon the degree of agglutination and
  destruction of the foetal red cells, various
  types of foetal haemolytic disease appear. Also
  termed as ERYTHROBLASTOSIS FOETALIS.
• Note The antibody has no effect on Rh-negative
  foetus.

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MANIFESTATIONS OF THE HEMOLYTIC DISEASE

• Clinical manifestations/effects of the hemolytic
  disease of the fetus and neonate are
• Hydrops fetalis
• Icterus gravis neonatorum
• Congenital anaemia of the newborn

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HYDROPS FETALIS

• This is the most serious form of Rh hemolytic
  disease.
• Excessive destruction of the foetal red cells
  leads to
• Severe anaemia,
• Tissue anoxemia and
• Metabolic acidosis.
• These have got adverse effects on the foetal
  heart and brain and on the placenta

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HYDROPS FETALIS CONT..

• Hyperplasia of the placental tissue occurs in an
  effort to increase the transfer of oxygen but the
  available fetal red cells (oxygen carrying cells)
  are progressively diminished due to hemolysis.
• 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 soon
  after.

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HYDROPS FETALIS CONT.

• The following are the diagnostic features
• Mother is Rh-negative
• Serological examination reveals presence of
  Rh-antibody
• There may be presence of polyhydramnios
• Previous history of affection of a baby due to
  hemolytic disease
• Sonography to detect edema in the skin, scalp
  and pleural or pericardial effusion and echogenic
  bowel

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HYDROPS FETALIS CONT

• Straight X-ray abdomen showingBuddha position
  of the fetus with a halo around the head due to
  edematous scalp
• The baby at birth looks pale and edematous with
  an enlarged abdomen due to ascites. There is
  enlargement of liver and spleen
• Placenta is large, pale and edematous with fluid
  oozing from it. The placental weight may be
  increased to about half or even almost equal to
  the fetal weight.
• There is undue persistence of Langhans layer with
  marked swelling of the villi. If the fetus is not
  hydropic, the placenta usually looks normal.

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HYDROPS FETALIS
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ICTERUS GRAVIS NEONATORUM

• This is a lesser form of foetal hemolysis.
• The baby is born alive without evidences of
  jaundice but soon develops it within 24 hours of
  birth.
• While the fetus is in-utero, there is destruction
  of fetal red cells with liberation of
  unconjugated bilirubin which is mostly excreted
  through the placenta into the maternal system. A
  portion of the bilirubin enters the amniotic
  fluid perhaps from the fetal lung or through the
  skin or across the surface of the placenta or
  cord.
• This is the reason why the baby is not born with
  jaundice

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ICTERUS GRAVIS NEONATORUM CONT

• But as soon as the umbilical cord is clamped,
  with continuing hemolysis, the bilirubin
  concentration is increased. Sooner or later the
  baby becomes jaundiced.
• The liver particularly of a premature baby fails
  to conjugate the excessive amount of bilirubin to
  make it soluble and nontoxic.
• If the bilirubin rises to the critical level of
  20 mg per 100 mL (340 micromol/Lnormal 30
  micromol/L), the bilirubin crosses the
  blood-brain barrier to damage the basal nuclei of
  the brain permanently producing the clinical
  manifestation of kernicterus.

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ICTERUS GRAVIS NEONATORUM
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CONGENITAL ANEMIA OF THE NEWBORN

• This is the mildest form of the disease.
• The hemolysis is going on slowly. Although the
  anemia develops slowly within first few weeks of
  life, the jaundice is not usually evident. The
  destruction of the red cells continues up to 6
  weeks after which the antibodies are not
  available for hemolysis.
• The liver and spleen are enlarged, the sites of
  extramedullary erythropoiesis.

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Rh incompatibility effects to the mother

• The impact of Rh incompatibility mainly falls on
  the baby. The mother may also be affected
  somewhat. There is increased incidence of
• Pre-eclampsia
• Polyhydramnios
• Big size baby( edematous baby) with its hazards
  
• Hypofibrinogenemia due to prolonged retention of
  dead fetus in the uterus

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Rh incompatibility effects to the motherconti..

• Postpartum hemorrhage due to big placenta and
  blood coagulopathy
• Maternal syndromeThe salient features are
  generalized edema, proteinuria and pruritus due
  to cholestasis. These features are ominous
  indicating imminent fetal death in utero.

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Management

• Blood typing at 1st visit (all pregnant)
• History of prior transfusion
• Previous pregnancies including abortions
• Previous administration of IgG
• Previous obstetric invasive procedure

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Antenatal investigations of Rh-negative mother

• 1. Approximation of the volume of foetal blood
  entering into the maternal circulation by
  KLEIHAUER-BETKE TEST
• For the presence of foetal cells in the maternal
  circulation. It is done using acid elution to
  note the number of foetal cells per 50 low power
  fields.
• 5cells per 50fields a bleed of 0.5ml

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Antenatal investigations of Rh-negative mother
conti

• 2. Indirect coombs test
• Is for detection of the IgG
• Done to all Rh-negative pregnant women
  irrespective of blood grouping or parity
• A) If indirect coombs test is negative at
  12weeks of pregnancy repeat
• at 28 and 36 weeks in primigravidae
• monthly at intervals from 24weeks onwards

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Antenatal investigations of Rh-negative mother
conti

• If positive , transfer to specialized centre and
  test for genotype of husband. (Rosette screening
  test )
• 3. Direct coombs test
• Is collection of cord blood for investigation.
  After quickly clamping the cord to minimize
  amount of antibody to cross to the foetus from
  the mother 5mls of blood is collected for the
  test.

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Methods of determining fetal status

• Titers determinationcoombs test
• Past obstetric history
• USS to detect oedema of the skin/scalp, pleural
  effusion, pericardial effusion, echogenic bowel
• Cordocentesis

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Management scheme

• Amniotic fluid analysis
• Based on Liley curve
• Mild or no hemolysis- zone 1
• Intermediate disease-zone 2
• severe, disease including development of hydrops
  zone 3

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Management scheme cont.. Other therapies for
foetal Rh immunization

• 1. Intrauterine foetal transfusion
• 2. Intraperitoneal transfusion
• 3. Intravascular transfusion
• 4. Other therapies
• High doses of intravenous immunoglobulin(IVIG)
• Exchange transfusion in the newborn
• 5. Phototherapy
• 6. Antibiotics

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OTHER BLOOD GROUP ISOIMMUNIZATION

• Other blood groups that may evoke immunoglobins
  capable of crossing the placenta and cause severe
  fetal hemolysis.
• Kell
• Duffy
• Kidd
• MNS
• Diego
• P. Lutheran
• Xg

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Prevention of Rh Incompatibility

• 1. To prevent active immunization
• To an unimmunised mother Rh anti-D
  immunoglobulin (IgG) is administered i/m
  following childbirth or abortion.
• Note Should be administered to the mother within
  72hours after delivery/abortion
• DOSE a) After delivery 300µgm i/m
• b) 50µgm i/m after abortion/ectopic
  pregnancy

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Prevention of Rh Incompatibility conti..

• 2) During pregnancy
• Rh negative women with NO antibody detected
  should have two doses of IgG i/m prophylaxis
• At 28 weeks 100µgm
• At 34 weeks 100µgm
• After birth within 72hours 300µgm i/m

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Prevention of Rh Incompatibility conti..

• 3) To prevent/minimize foeto-maternal bleed
• A) Caution during C/S
• - Prevent blood spilling into peritonial cavity
• - Avoid manual removal of placenta
• B) Avoid procedures such as
• - Amniocentesis
• - External version
• 4) Avoid giving Rh-positive blood to an
  Rh-negative female

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References

• DC Dutta (2015) Textbook of Obstetrics 8th
  Edition ((P) Ltd New Delhi) PG 387-397
• Kevin P. Hanretty (2003) Obstetri Illustrated
  6th edition (Elsevier Ltd Tottenham Court Road)
  Pg 104-113

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Read the details about the Liley curve