Last Updated on May 25, 2020
Hemolytic disease of the newborn is a condition that develops in a fetus, when the maternal antibodies pass through the placenta and attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells.
The condition of the fetus could be from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur.
Erythroblasts (immature red blood cells) are present in the fetal blood, and so these forms of the disease can be called erythroblastosis fetalis.
Another name for the condition is hemolytic disease of the fetus and newborn
The condition affects an estimated 3 in 100,000 to 80 in 100,000 patients annually.
Three antibodies are associated with severe fetal disease: anti-RhD, anti-Rhc, and anti-Kell(K1).
Prevention is available against anti-RhD type only and this prevention has decreased the incidence of Rh disease dramatically.
Recent improvements in intrauterine management of these fetuses have improved the prognosis.
Rh sensitization normally does not cause a problem in the first pregnancy. Most problems occur in future pregnancies with another Rh-positive baby. The condition is called erythroblastosis fetalis during pregnancy. Once the baby is born, it’s called hemolytic disease of the newborn.
Read more about Rh Immune Globulin
A history of hydropic birth increases the risk of fetal hydrops in the next pregnancy to 90%.
Types
Rhesus system
-
- rhesus D (Rh disease) – most common form
- rhesus E
- rhesus c
- Combination of C and E
Kell system
-
-
- anti-K 1 – second most common form
- anti-K 2, anti-K 3 and anti-K 4 antibodies – rare
-
Kell sensitization results in hemolysis and suppression of erythropoiesis as the Kell antigen is expressed on the surface of erythroid progenitors. This causes severe fetal disease at a lower maternal antibody titer than in Rhesus disease.
ABO system
- Range from mild to severe, but generally a mild disease.
- anti-A antibodies
- anti-B antibodies
Hemolysis associated with ABO incompatibility exclusively occurs in type-O mothers with fetuses who have type A or type B blood.
Read more about Hemolytic Anemia- Causes and Treatment
In mothers with type A or type B, naturally occurring antibodies are of the IgM class and do not cross the placenta. But 1% of type-O mothers have high titers of the antibodies of IgG class against both A and B which cross the placenta.
Rarely it has been shown in type-A mothers with type-B infants with a high titer of anti-B IgG.
Hemolysis due to anti-A is more common than hemolysis due to anti-B but, hemolysis due to anti-B IgG can be severe.
A and B antigens are widely expressed in various tissues besides RBCs. Fetal RBCs appear to have less surface expression of A or B antigen. This leads to the low incidence of significant hemolysis in affected neonates with ABO incompatibility.
Rather, hyperbilirubinemia is a major manifestation.
A large number of spherocytes and few erythroblasts are seen on peripheral blood film [ Rh incompatibility reveals a large number of nucleated RBCs and few spherocytes].
Read more about Abnormal RBC Types and Shapes
Other
Kidd, Lewis, Duffy, MN, P, and others.
Pathophysiology of Hemolytic Disease of Newborn
During the first pregnancy, the sensitization of Rh-negative mother to Rh-positive red cells occurs as a result of symptomatic fetomaternal hemorrhage during pregnancy. The incidence of fetomaternal hemorrhage is about 75% of all pregnancies [Kleihauer-Betke acid elution technique].
7%, 16%, and 29% of mothers during their first, second, and third trimesters have fetomaternal hemorrhage respectively.
Procedures such as amniocentesis, chorionic villus sampling, and cordocentesis increase the risk.
After the initial exposure IgM antibodies are produced [do not cross the placenta]. IgG is late to appear and can cross the placenta.
The risk of Rh immunization after the delivery of the first child to a nulliparous Rh-negative mother is 16% if the Rh-positive fetus is ABO compatible with its mother [ 2% if the fetus is ABO-incompatible (RBCs get rapidly destroyed in the maternal circulation)].
After an abortion, it is 2-5%.
Rh immunization is also dependent on the amount of fetomaternal hemorrhage
- 3% with < 0.1 mL
- 22% with >0.1 mL
In a subsequent pregnancy, repeat exposure to the same antigen rapidly induces the production of IgG maternal anti-D antibodies. These cross the placenta, enter into the fetal circulation and attach to Rh antigen on fetal RBCs. These antibody-coated RBCs are lysed by macrophages and natural killer lymphocytes.
Following changes are seen in the fetus
- Reticulocytosis
- Anemia
- Increase in venous lactate
Hydrops fetalis occurs when fetal Hb deficit exceeds 7 g/dL for the gestational age. It starts as fetal ascites and evolves into pleural effusions and generalized edema.
The reason for hydrops is
- Hypoalbuminemia [due to poor liver function]
- Increased capillary permeability
- Iron overload secondary to hemolysis
- Increased venous pressures due to poor cardiac function.
Severe anemia stimulates fetal erythropoiesis in the liver, spleen, bone marrow, and extramedullary sites, such as the skin and placenta.
Displacement and destruction of hepatic parenchyma by erythroid cells result in dysfunction and hypoproteinemia.
Extramedullary hematopoiesis can lead to hepatosplenomegaly, portal hypertension, and ascites.
Heme from destroyed red blood cells is converted to unconjugated bilirubin but hyperbilirubinemia becomes apparent only in the delivered newborn because the placenta effectively metabolizes bilirubin.
The suppression of erythropoiesis by intravascular transfusion of adult Hb to an anemic fetus can also contribute to anemia.
Clinical Presentation
On history, pointers to the risk of severe hemolytic disease of the newborn are
- Mothers with previous children with hemolytic disease
- Rising maternal antibody titers
- Rising amniotic fluid bilirubin concentration
- Fetal hydrops
- Decreasing hemoglobin level
During pregnancy, the fetus may display the following
- Yellow amniotic fluid with the presence of bilirubin, seen on an amniocentesis
- Organomegaly – hepatomegaly, splenomegaly, or cardiomegaly
- Fluid in the abdomen, lungs, or scalp on ultrasonograph
After birth, the signs vary with the severity of the disease.
Jaundice, pallor, hepatosplenomegaly, and fetal hydrops are seen in severe cases.
Jaundice typically manifests at birth or in the first 24 hours after birth.
Diagnosis and Treatment
In pregnancy, the condition is suggested by
- Positive maternal antenatal antibody
- Diagnosis of anemia in the fetus
- Fetal hydrops
In the newborn, the condition is characterized by one or more of the following findings
- Rapidly progressive severe hyperbilirubinemia or prolonged hyperbilirubinemia
- Positive neonatal direct Coombs test (direct antiglobulin test)
- Hemolysis on blood film findings
During Pregnancy
At the first prenatal visit, all women are screened for blood type, Rh type, and anti-Rh0(D) and other antibodies that can cause erythroblastosis fetalis.
#If women have Rh-negative blood and
Tests negative for the antibodies
- Nothing further to be done
Tests positive for the antibodies
- Determine the father’s blood type and zygosity
#If the father has Rh-negative blood and is negative for the antigen for the antibody identified in the mother
- no further testing is necessary.
If he has Rh-positive blood or has the antigen
- Maternal anti-Rh antibody titers are measured every 2 to 4 wk after 20 wk.
1:8 to 1:32 is the critical value of titers [varies from lab to lab].
# If the critical value is exceeded
- Measure fetal middle cerebral artery blood at intervals of 1 to 2 to detect high-output heart failure, indicating a high risk of anemia.
If the flow is elevated for gestation [not reliable after 35 weeks], either a sample of fetal blood is obtained to determine fetal Rh type [not done commonly now] or decision for intravascular transfusion is considered.
Repeated blood transfusions are given with an aim to carry the pregnancy to 32-35 weeks [lung maturity occurs around that time] when delivery can be considered.
If fetal blood is Rh-negative or if middle cerebral artery blood flow remains normal, pregnancy can continue to term untreated.
A critical titer of 1:32, which indicates that a high risk of fetal hydrops has been reached. At this point, the fetus requires very intense monitoring for signs of anemia and fetal hydrops. In Kell alloimmunization, hydrops can occur at low maternal titers because of suppressed erythropoiesis.
Plasmapheresis
Plasmapheresis with partial replacement using 5% albumin and intravenous immunoglobulin has been shown to be moderately effective.
These act by blocking Fc receptors in the placenta, reduce antibody transport across to the fetus, and block Fc receptors on the phagocytes in the fetal reticuloendothelial system.
But these techniques only delay the need for intravascular transfusion until 20-22 weeks gestation. After that, these procedures can be performed at a more acceptable risk.
Management of the Newborn
50% of newborns with positive direct antibody test results have a mild hemolytic disease and require no treatment apart from phototherapy for hyperbilirubinemia.
However, monitoring their Hb levels is required as these newborns are at risk of developing severe late anemia by 3-6 weeks of life.
Moderate hemolytic disease [ 25% of affected newborns] is characterized by moderate anemia and increased cord bilirubin levels.
Though not clinically jaundiced at birth, these children rapidly develop unconjugated hyperbilirubinemia in the first 24 hours of life.
Peripheral smear shows numerous nucleated RBCs, decreased platelets, and, occasionally, a large number of immature granulocytes.
These newborns often have hepatosplenomegaly and are at risk of developing bilirubin encephalopathy without adequate treatment. The treatment consists of exchange transfusion with type-O Rh-negative fresh RBCs, intensive phototherapy, and intravenous immunoglobulins.
Infants with severe hemolytic disease [ 25%] are either stillborn or hydropic at birth. Hydropic fetuses are associated with poor survival.
Early recognition and antenatal management may help to improve the prognosis.
In the absence of a positive direct Coombs test result, other causes of pathologic jaundice should be considered which include
- Intrauterine congenital infections
- Erythrocyte membrane defects
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary pyropoikilocytosis
- RBC enzyme deficiencies
- Glucose-6-phosphate dehydrogenase deficiency
- Pyruvate kinase deficiency
- Triosephosphate isomerase deficiency
- Enclosed hemorrhages
- Hypothyroidism
- Gastrointestinal obstruction
- Metabolic disorders
- Hemoglobinopathies (eg, α-thalassemia major)
- Cardiac failure due to dysrhythmia
- Congenital heart defects.
Intramuscular Tin (Sn) porphyrin a potent inhibitor of heme oxygenase, has been shown to reduce the production of bilirubin in neonates with ABO incompatibility. This reduces the need for exchange transfusion and the duration of phototherapy
Heme oxygenase is the enzyme that catalyzes the rate-limiting step in the production of bilirubin from heme,
Phototherapy
Phototherapy is indicated in the term infant with hemolytic disease of the newborn immediately after birth due to Rh disease and due to ABO incompatibility
- Immediately after birth in all preterms who weigh less than 2500 g
- In others, at following ages and levels of total serum bilirubin.
- Just born [Cord blood] – >3.5 mg/dL
- 12 hours – > 10 mg/dL
- 18 hours – > 12 mg/dL
- 24 hours > 14 mg/dL
- 2-3 days – >15 mg/dL
Exchange Transfusion
Exchange transfusion removes circulating bilirubin and antibody-coated RBCs, replacing them with RBCs compatible with maternal serum and providing albumin with new bilirubin binding sites.
Exchange transfusion should be considered in newborns
- Born > 38 weeks’ with a bilirubin-to-albumin ratio of 7.2
- Born at 35-37 weeks’ gestation with a bilirubin-to-albumin ratio of 6.8.
Intravenous Immunoglobulins
IVIG has been shown to reduce the need for exchange transfusion in hemolytic disease of the newborn due to Rh or ABO incompatibility.
Prevention of Hemolytic Disease of the Newborn
Consider the following in patients with hemolytic disease of the newborn:
Rh immune globin (RhIG) is administered to all unsensitized Rh-negative women at 28 weeks’ gestation with an additional dose administered soon after birth if the infant is Rh-positive, irrespective of the ABO status of the baby.
It is also recommended after any event known to be associated with transplacental hemorrhage such as
- Spontaneous or elective abortion
- Ectopic pregnancy
- Amniocentesis
- Chorionic villous sampling,
- Fetal blood sampling
- Hydatiform mole
- Fetal death in late gestation
- Blunt abdominal trauma
- External cephalic version.
Complications of Hemolytic Disease of the Newborn
- Bilirubin encephalopathy
- Occurs due to high levels of bilirubin
- Late anemia of infancy
- Suppression of fetal erythropoiesis from transfusion of adult Hb during intrauterine or exchange transfusion
- Continued destruction of neonatal RBCs
- Administration of recombinant human erythropoietin is effective