Hemolytic disease of the newborn

Not to be confused with Hemorrhagic disease of the newborn.

HDN

Classification and external resources
Specialty	pediatrics
ICD-10	P55
ICD-9-CM	773
DiseasesDB	5545
MedlinePlus	001298
eMedicine	ped/959
Patient UK	Hemolytic disease of the newborn
MeSH	D004899

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis,^[1] 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 antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells (hemolysis). The fetus can develop reticulocytosis and anemia. 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 (immature red blood cells) are present in the fetal blood, and so these forms of the disease can be called erythroblastosis fetalis (or erythroblastosis foetalis).

HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance of pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. In order of incidence, the types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell.

Signs and 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 discoloration 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 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 have received a therapeutic blood transfusion. ABO blood group system and the D antigen of the Rhesus (Rh) 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 or IgG anti-A and anti-B antibodies early in life. Women of blood type O are more prone than women of types A and B to making IgG anti-A and anti-B antibodies, and these IgG antibodies are able to cross the placenta. For unknown reasons, the incidence of maternal antibodies against type A and B antigens of the IgG type that could potentially cause hemolytic disease of the newborn is greater than the observed incidence of "ABO disease." About 15% of pregnancies involve a type O mother and a type A or type B child; only 3% of these pregnancies result in hemolytic disease due to A/B/O incompatibility. In contrast to antibodies to A and B antigens, Rhesus antibodies are generally not produced from exposure to environmental antigens.

Types (classified by serology)

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 (i.e. anti-Rhc and anti-RhE antibodies occurring together) - can be severe
Kell system
- anti-Kell hemolytic disease of the newborn
  - anti-K₁ 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-K₂, anti-K₃ and anti-K₄ antibodies - rare
Other blood group antibodies (Kidd, Lewis, Duffy, MN, P and others).

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 who are pregnant with a rhesus-positive infant are offered Rh immune globulin (RhIG) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood 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 immunological responses that result in antibody production.

Complications and similar conditions

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

Other animals

Main article: Neonatal isoerythrolysis

Hemolytic disease of the newborn is most commonly seen in kittens (where it is known as "fading kitten syndrome") and foals. It has also been reported in puppies.

References

↑ "erythroblastosis fetalis" at Dorland's Medical Dictionary

External links

Geifman-Holtzman, O; Wojtowycz M; Kosmas E; Artal R (1997). "Female allo-immunization with antibodies known to cause hemolytic disease". Obstetrics and Gynecology. 89 (2): 272–275. doi:10.1016/S0029-7844(96)00434-6. ISSN 0029-7844. PMID 9015034.
Mollison, PL; Engelfriet CP; Contreras M (1997). Blood Transfusion in Clinical Medicine (10th ed.). Oxford, UK: Blackwell Science. ISBN 0-86542-881-6.
Blood Groups and Red Blood Cell Antigens: Hemolytic disease of the newborn

Certain conditions originating in the perinatal period / fetal disease (P, 760–779)

Maternal factors and
complications of pregnancy,
labour and delivery

placenta:	Placenta praevia Placental insufficiency Twin-to-twin transfusion syndrome

chorion/amnion:	Chorioamnionitis

umbilical cord:	Umbilical cord prolapse Nuchal cord Single umbilical artery

Length of gestation
and fetal growth

Birth trauma

By system

Respiratory	Intrauterine hypoxia Infant respiratory distress syndrome Transient tachypnea of the newborn Meconium aspiration syndrome pleural disease Pneumothorax Pneumomediastinum Wilson–Mikity syndrome Bronchopulmonary dysplasia

Cardiovascular	Pneumopericardium Persistent fetal circulation

Haemorrhagic and hematologic disease	Vitamin K deficiency Haemorrhagic disease of the newborn HDN ABO Anti-Kell Rh c Rh D Rh E Hydrops fetalis Hyperbilirubinemia Kernicterus Neonatal jaundice Velamentous cord insertion Intraventricular hemorrhage Germinal matrix hemorrhage Anemia of prematurity

Digestive	Ileus Necrotizing enterocolitis Meconium peritonitis

Integument and thermoregulation	Erythema toxicum Sclerema neonatorum

Nervous system	Periventricular leukomalacia

Musculoskeletal	Gray baby syndrome muscle tone Congenital hypertonia Congenital hypotonia

Infectious

Other

Hypersensitivity and autoimmune diseases (279.5–6)

Type I/allergy/atopy
(IgE)

Foreign	Atopic eczema Allergic urticaria Allergic rhinitis (Hay fever) Allergic asthma Anaphylaxis Food allergy common allergies include: Milk Egg Peanut Tree nut Seafood Soy Wheat Penicillin allergy

Autoimmune	Eosinophilic esophagitis

Type II/ADCC

- IgM
- IgG

Foreign

Hemolytic disease of the newborn

Autoimmune

Cytotoxic	Autoimmune hemolytic anemia Immune thrombocytopenic purpura Bullous pemphigoid Pemphigus vulgaris Rheumatic fever Goodpasture's syndrome Guillain–Barré syndrome

"Type V"/receptor	Graves' disease Myasthenia gravis Pernicious anemia

Type III
(Immune complex)

Foreign	Henoch–Schönlein purpura Hypersensitivity vasculitis Reactive arthritis Farmer's lung Post-streptococcal glomerulonephritis Serum sickness Arthus reaction

Autoimmune	Systemic lupus erythematosus Subacute bacterial endocarditis Rheumatoid arthritis

Type IV/cell-mediated
(T cells)

Foreign	Allergic contact dermatitis Mantoux test

Autoimmune	Diabetes mellitus type 1 Hashimoto's thyroiditis Multiple sclerosis Coeliac disease Giant-cell arteritis Postorgasmic illness syndrome Reactive arthritis

GVHD	Transfusion-associated graft versus host disease

Unknown/
multiple

Foreign	Hypersensitivity pneumonitis Allergic bronchopulmonary aspergillosis Transplant rejection Latex allergy (I+IV)

Autoimmune	Sjögren's syndrome Autoimmune hepatitis Autoimmune polyendocrine syndrome APS1 APS2 Autoimmune adrenalitis Systemic autoimmune disease

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