ERYTHROBLASTOSIS FETALIS

ERYTHROBLASTOSIS FETALIS.

Hemolytic disease of the newborn, also known as Hemolytic disease of the fetus and newborn, HDN, HDFN, or Erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack the red blood cells in the fetal circulation; the red cells are broken down and the fetus can develop reticulocytosis and anaemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood and so these forms of the disease can be called erythroblastosis fetalis (or erythroblastosis foetalis).

Erythroblastosis fetalis is hemolytic anemia in the fetus or neonate caused by transplacental transmission of maternal antibodies to fetal RBCs. The disorder usually results from incompatibility between maternal and fetal blood groups, often Rh₀(D) antigens. Diagnosis begins with prenatal maternal antigenic and antibody screening and may require paternal screening, serial measurement of maternal antibody titers, and fetal testing. Treatment may involve intrauterine fetal transfusion or neonatal exchange transfusion. Prevention is Rh₀(D) immune globulin injection for women at risk.

Erythroblastosis fetalis classically results from Rh₀(D) incompatibility, which may develop when a woman with Rh-negative blood is impregnated by a man with Rh-positive blood and conceives a fetus with Rh-positive blood (see also Perinatal Hematologic Disorders: Hemolysis). Other fetomaternal incompatibilities that can cause erythroblastosis fetalis involve the Kell, Duffy, Kidd, MNSs, Lutheran, Diego, Xg, P, Ee, and Cc antigen systems, as well as other antigens. Incompatibilities of ABO blood types do not cause erythroblastosis fetalis.

Pathophysiology

Fetal RBCs normally move across the placenta to the maternal circulation throughout pregnancy. Movement is greatest at delivery or termination of pregnancy. Movement of large volumes (eg, 10 to 150 mL) is considered significant fetomaternal hemorrhage; it can occur after trauma and sometimes after delivery or termination of pregnancy. In women who have Rh-negative blood and who are carrying a fetus with Rh-positive blood, fetal RBCs stimulate maternal antibody production against the Rh antigens. The larger the fetomaternal hemorrhage, the more antibodies produced. The mechanism is the same when other antigen systems are involved; however, Kell antibody incompatibility also directly suppresses RBC production in bone marrow.

Other causes of maternal anti-Rh antibody production include injection with needles contaminated with Rh-positive blood and inadvertent transfusion of Rh-positive blood.

No complications develop during the initial sensitizing pregnancy; however, in subsequent pregnancies, maternal antibodies cross the placenta and lyse fetal RBCs, causing anemia, hypoalbuminemia, and possibly high-output heart failure or fetal death. Anemia stimulates fetal bone marrow to produce and release immature RBCs (erythroblasts) into fetal peripheral circulation (erythroblastosis fetalis). Hemolysis results in elevated indirect bilirubin levels in neonates, causing kernicterus (see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Kernicterus). Usually, isoimmunization does not cause symptoms in pregnant women.

Causes

Erythroblastosis fetalis develops in an unborn infant when the mother and baby have different blood types. The mother produces substances called antibodies that attack the developing baby's red blood cells.
The most common form of erythroblastosis fetalis is ABO incompatibility, which can vary in severity.
The less common form is called Rh incompatibility, which can cause very severe anemia in the baby.

ABO incompatibility

ABO incompatibility is a reaction of the immune system that occurs if two different and not compatible blood types are mixed together.

Causes

A, B, and O are the three major blood types. The types are based on small substances (molecules) on the surface of the blood cells. In people who have different blood types, these molecules act as immune system triggers (antigens).

Each person has a combination of two of these surface molecules. Type O lacks any molecule. The different blood types are:

• Type A (AA or AO molecules)
• Type B (BB or BO molecules)
• Type AB
• Type O

People who have one blood type form proteins (antibodies) that cause their immune system to react against other blood types. Being exposed to another type of blood can cause a reaction. This is important when a patient needs to receive blood (transfusion) or have an organ transplant. The blood types must be matched to avoid an ABO incompatibility reaction.

For example:

• A patient with type A blood will react against type B or type AB blood
• A patient with type B blood will react against type A or type AB blood
• A patient with type O blood will react against type A, type B, or type AB blood

Because type O lacks any surface molecules, type O blood does not cause an immune response. This is why type O blood cells can be given to patients of any blood type. People with type O blood are called "universal donors." However, people with type O can only receive type O blood.
Since antibodies are in the liquid part of blood (plasma), both blood and plasma transfusions must be matched to avoid an immune reaction.

Symptoms

The following are symptoms of transfusion reactions:

• Back pain
• Blood in urine
• Feeling of "impending doom"
• Fever
• Yellow skin (jaundice)

Exams and Tests

• Bilirubin level is high
• Complete blood count (CBC) shows damaged red blood cells, may also show mild anemia
• Lab testing of patient's and donor's blood shows that they are not compatible

Treatment

Treatment may include:

• Drugs used to treat allergic reactions (antihistamines)
• Drugs used to treat swelling and allergies (steroids)
• Fluids given through a vein (intravenous)
• Medicines to raise blood pressure if it drops too low

Rh incompatibility

Rh incompatibility is a condition that develops when a pregnant woman has Rh-negative blood and the baby in her womb has Rh-positive blood.

Causes

During pregnancy, red blood cells from the fetus can get into the mother's bloodstream as she nourishes her child through the placenta.
If the mother is Rh-negative, her immune system treats the Rh-positive fetal cells as if they were a foreign substance and makes antibodies against the fetal blood cells. These anti-Rh antibodies may cross the placenta into the developing baby, where they destroy the baby's circulating red blood cells.
When red blood cells are broken down, they make bilirubin, which causes an infant to become yellow (jaundiced). The level of bilirubin in the infant's bloodstream may range from mild to dangerously high.
Firstborn infants are often not affected -- unless the mother has had previous miscarriages or abortions, which could have sensitized her system -- as it takes time for the mother to develop antibodies against the fetal blood. However, second children who are also Rh-positive may be harmed.
Rh incompatibility develops only when the mother is Rh-negative and the infant is Rh-positive. This problem has become uncommon in the United States and other places that provide good prenatal care. Special immune globulins, called RhoGAM, are now used to prevent RH incompatibility.

Symptoms

Rh incompatibility can cause symptoms ranging from very mild to deadly. In its mildest form, Rh incompatibility causes destruction of red blood cells.
Symptoms may include:

• Low muscle tone (hypotonia)
• Developmental delay
• Increased amount of amniotic fluid (polyhydramnios)
• Yellowing of the skin and whites of the eyes (jaundice)

Exams and Tests

There may be:

• A positive direct Coombs test result
• Higher than normal levels of bilirubin in the baby's cord blood
• Signs of red blood cell destruction in the infant's blood

Treatment

Since Rh incompatibility is almost completely preventable with the use of RhoGAM, prevention remains the best treatment. Treatment of the already affected infant depends on the severity of the condition.
Mild Rh incompatibility may be treated with:

• Aggressive hydration
• Phototherapy using bilirubin lights 

• ERYTHROBLASTOSIS FETALIS:

• The baby's body tries to compensate for the anemiacaused by the mother's antibodies by releasing immature red blood cells, called erythroblasts. The overproduction of erythroblasts can cause the liver andspleen to become enlarged, potentially causing liver damage or a ruptured spleen. Excess erythroblast production means that fewer of other types of bloodcells are produced, such as platelets and other factors important for bloodclotting. Excessive bleeding can be a complication. The destroyed red blood cells release the blood's red pigment (hemoglobin) which degrades into a yellow substance called bilirubin. Bilirubin is normally produced as red blood cells die, but the body can only handle a low level of bilirubin. In erythroblastosis fetalis, high levels of bilirubin accumulate and cause hyperbilirubinemia, a condition in which the baby becomes jaundiced, a yellowish tone of theeyes and skin. If hyperbilirubinemia cannot be controlled, the baby developskernicterus, in which bilirubin is deposited in the brain and may cause permanent damage. Other symptoms include high levels of insulin and low blood sugar, as well as a condition called hydrops fetalis. Hydrops fetalis causes fluids to accumulate within the baby's body, making it look swollen. This inhibits normal breathing and can interfere with lung growth if it continues for anextended period. Hydrops fetalis and anemia can also contribute to heart problems.
  

  

  Erythroblastosis fetalis can be predicted before birth by determining the mother's blood type. If she is Rh-negative, the father's blood is tested to determine whether he is Rh-positive. If the father is Rh-positive, the mother's blood will be checked for antibodies against the Rh factor. A blood test thatdemonstrates no antibodies is repeated at week 26 or 27 of the pregnancy. Blood incompatibility is uncovered through blood tests such as the Coombs test,and others. When a mother has antibodies against her unborn infant's blood, the antibodies are monitored and if levels increase, amniocentesis, fetal umbilical cord blood sampling, and ultrasound are used to assess any effects on the baby. If the baby is in danger, and the pregnancy is at least 32-34 weeksalong, labor is induced. Under 32 weeks, the baby is given blood transfusions while in the mother's uterus. After birth, the severity of the baby'ssymptoms is assessed. Transfusions may be necessary to treat anemia, hyperbilirubinemia, and bleeding. Hyperbilirubinemia is also treated with phototherapy, oxygen and intravenous fluids, or drugs. Treatment of minor symptoms is typically successful and the baby will not suffer long-term problems. Erythroblastosis is a serious condition for approximately 4,000 babies annually, 15%of whom die before birth. Babies who survive pregnancy may develop kernicterus, which can lead to deafness, speech problems, cerebral palsy, or mental retardation. Extended hydrops fetalis can inhibit lung growth and contribute toheart failure. These serious complications are life threatening, but with good medical treatment, the fatality rate is very low. With any pregnancy, blood typing is a universal precaution against blood incompatibility disease. If an Rh-negative woman gives birth to an Rh-positive baby, she is injected with immunoglobulin G, a type of antibody protein, within 72 hours of the birth, to destroy fetal blood cells in her bloodstream before her immune system can react to them. 
• Symptoms
• Hemolysis leads to elevated bilirubin levels. After delivery bilirubin is no longer cleared (via the placenta) from the neonate's blood and the symptoms of jaundice (yellowish skin and yellow discolouration of the whites of the eyes) increase within 24 hours after birth. Like any other severe neonatal jaundice, there is the possibility of acute or chronic kernicterus.
• Profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress. The prenatal manifestations are known as hydrops fetalis; in severe forms this can include petechiae and purpura. The infant may be stillborn or die shortly after birth Causes
  Antibodies are produced when the body is exposed to an antigen foreign to the make-up of the body. If a mother is exposed to a foreign antigen and produces IgG (as opposed to IgM which does not cross the placenta), the IgG will target the antigen, if present in the fetus, and may affect it in utero and persist after delivery. The three most common models in which a woman becomes sensitized toward (i.e., produces IgG antibodies against) a particular antigen are:
  • Fetal-maternal hemorrhage can occur due to trauma, abortion, childbirth, ruptures in the placenta during pregnancy, or medical procedures carried out during pregnancy that breach the uterine wall. In subsequent pregnancies, if there is a similar incompatibility in the fetus, these antibodies are then able to cross the placenta into the fetal bloodstream to attach to the red blood cells and cause hemolysis. In other words, if a mother has anti-RhD (D being the major Rhesus antigen) IgG antibodies as a result of previously carrying a RhD-positive fetus, this antibody will only affect a fetus with RhD-positive blood.
  • The woman may receive a therapeutic blood transfusion. ABO blood group system and the D antigen of the Rhesus blood group system typing are routine prior to transfusion. Suggestions have been made that women of child bearing age or young girls should not be given a transfusion with Rhc-positive blood or Kell₁-positive blood to avoid possible sensitization, but this would strain the resources of blood transfusion services, and it is currently considered uneconomical to screen for these blood groups. HDFN can also be caused by antibodies to a variety of other blood group system antigens, but Kell and Rh are the most frequently encountered.
  • The third sensitization model can occur in women of blood type O. The immune response to A and B antigens, that are widespread in the environment, usually leads to the production of IgM anti-A and IgM anti-B antibodies early in life. On rare occasions, IgG antibodies are produced. In contrast, Rhesus antibodies are generally not produced from exposure to environmental antigens.
  

   Serological diagnoses

  • ABO system
    • ABO hemolytic disease of the newborn can range from mild to severe, but generally it is a mild disease.
      • anti-A antibodies
      • anti-B antibodies
  • Rhesus system
    • rhesus D hemolytic disease of the newborn (often called Rh disease) is the most common form of severe HDN. The disease varies from mild to severe.
    • rhesus E hemolytic disease of the newborn is a mild condition
    • rhesus c hemolytic disease of the newborn can range from a mild to severe disease - is the third most common form of severe HDN
    • rhesus e hemolytic disease of the newborn - rare
    • rhesus C hemolytic disease of the newborn - rare
    • antibody combinations (ie anti-Rhc and anti-RhE antibodies occurring together) - can be severe
  • Kell system
    • anti-Kell hemolytic disease of the newborn
      • anti-K ₁ antibodies - disease ranges from mild to severe - over half of the cases are caused by multiple blood transfusions - is the second most common form of severe HDN
      • anti-K ₂ ,anti-K ₃ and anti-K ₄ antibodies - rare
  • Other blood group antibodies 
  
   Diagnosis
  The diagnosis of HDN is based on history and laboratory findings:
  Blood tests done on the newborn baby
  
  • Biochemistry tests for jaundice
  • Peripheral blood morphology shows increased reticulocytes. Erythroblasts (also known as nucleated red blood cells) occur in moderate and severe disease.
  • Positive direct Coombs test (might be negative after fetal interuterine blood transfusion)
  Blood tests done on the mother
  
  • Positive indirect Coombs test

   Treatment

  Before birth, options for treatment include intrauterine transfusion or early induction of labor when pulmonary maturity has been attained, fetal distress is present, or 35 to 37 weeks of gestation have passed. The mother may also undergo plasma exchange to reduce the circulating levels of antibody by as much as 75%.
  After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion with a blood type compatible with both the infant and the mother, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
  Rhesus-negative mothers who have had a pregnancy with/are pregnant with a rhesus-positive infant are given Rh immune globulin (RhIG) at 28 weeks during pregnancy and within 72 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunonological responses that result in antibody production.
  

   Complications

  Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin.
  

   Similar conditions

  Similar conditions include acquired hemolytic anemia, congenital toxoplasma and syphilis infection, congenital obstruction of the bile duct and cytomegalovirus infection.
  

   In animals

  
  

  Mule foal, 7-days-old, in the last stage of hemolytic disease; symptoms appeared only on Day 6
  Hemolytic disease is a well-known condition in newborn foals, especially in Thoroughbreds and mules. Mares or jennies which have been sensitized by a previous pregnancy develop antibodies by fetal blood cells crossing the placental barrier. The iso-antibodies do not transcend the fetal barrier, but are present in colostrum. They will enter the bloodstream of the foal only after absorption of colostrum immunoglobulins, in the first days of life. Hence, hemolytic disaese will develop only after birth : first to 4th day in foal  and 3 to 7 days in newborn mules.
  Affected animals show lethargy, recumbency, tachycardia, and progressive icterus of eye and mouth mucosae, which rapidly leads to death.
  The condition is also described in newborn pigs and other animals