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Haemolytic Disease of the New Born (HDN)

About Dr Amer Hussain Agha

Introduction
HDN and fetus is the destruction of the red blood cells of the fetus and neonate by antibodies produced by the mother. The mother can be stimulated to form the antibodies by previous pregnancy or transfusion. HDN is the result of the passage of IgG antibodies from the maternal circulation across the placenta into the circulation of the fetus where they react with fetal red cells and mediate destruction by the fetal reticuloendothelial system (RES).

Only antibodies of the IgG class are actively transported across the placenta; other classes , such as IgA and IgM, are not. Usually in the case of Rh disease, the Rh+ve first born infant of an Rh-ve mother is unaffected because the mother has not yet been immunized.
During gestation, and particularly at delivery when the placenta separates from the uterus, variable numbers of fetal RBCs enter the maternal circulation. These fetal cells, carrying Rh antigen inherited from the father, immunize the mother and stimulate the production of anti-D. Once the mother is immunized to Rh antigen, all subsequent offspring inheriting the D antigen will be affected.
The maternal anti-D will cross the placenta and bind to the fetal Rh+ve cells. The sensitized RBCs are destroyed by the fetal reticuloendothelial system, resulting in anaemia.

Pathogenesis
- A Rh negative women has a pregnancy with a Rh positive fetus.
- Rh positive fetal red cells cross into the maternal circulation ( usually at parturition ) and sensitize the mother to form anti Rh antibodies ( anti – D ).
- Sensitization is more likely, if the mother and fetus are ABO compatible.
- The mother could also be sensitized by a previous miscarriage, aminocentesis or other trauma to the placenta or by blood transfusion.
- Anti – D antibodies crosses the placenta to the fetus during the next pregnancy with a Rh D positive fetus, coats the fetal red cells with antibody and results in RE system destruction of these cells, causing anaemia and jaundice. 

Pathogenesis
Foetomaternal 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.
Factors Affecting Immunization And Severity:
1- Antigenic Exposure:
· During gestation, (0.4%-7.0%).
· Aminocentesis and Chorionic villus sampling.
· Trauma to abdomen.
· Delivery (1 ml of fetal RBCs can immunize the mother).

2- Host Factors:
The ability to produce antibody in response to antigenic exposure varies depending on complex genetic factors.

3- Immunoglobulin Class:
Of the 4 sub classes of IgG antibody, IgG1 and IgG3 are more efficient in RBC hemolysis, than IgG2 and IgG4. Therefore the subclass(es) in the mother can effect the severity of the HDN.

4- Antibody Specificity:
Of all the RBC antigens, Rh(D) is the most antigenic. The other Rh antibodies such as C,E,c, and e have been associated with moderate to severe cases of HDN, but less potent than D. 

5- Influence of ABO Group:
When the mother is ABO incompatible with the fetus (major incompatibility), the incidence of detectable fetomaternal hemorrhage decreases. WHY?
(e.g; mother is O, and fetus is A or B)

Clinical Features
A- Severe Disease :
Intrauterine death from hydrops foetalis or still birth.

B- Moderate Disease :
The baby is born with ;
- Severe anaemia and jaundice. 
- Pallor, tacchycardia, oedema and hepatosplenomegaly.
- Deposition of bile pigment in the basal ganglia may lead to KERNICTERUS.
- Central nervous system damage with generalized spasticity and possible subsequent mental deficiency.
- Deafness and epilepsy.

C- Mild Disease:
- Mild anaemia with or without jaundice.

Diagnosis:
Serologic Testing of Parents:
· ABO and Rh testing for D and Du antigen.
· Antibody detection test (Antibody Screen).
· Paternal Phenotype.
· Rh antibody titer.
· Aminocentesis.

Serologic Testing of the Newborn Infant:
· ABO grouping.(only forward grouping ?).
· Rh typing.
· Direct Antiglobulin Test (DAT).

Laboratory Findings at Birth
- Cord Blood :
- Anaemia ( Hb = < 16 g / dl ).
- High reticulocyte count.
- Baby is Rh – positive.
- Serum bilirubin is raised.
- Peripheral film :
Many erythroblasts are seen. This condition is known as Erthroblastosis Foetalis.
- Mother is Rh- D negative, with high plasma levels of anti – D antibody.

Treatment
- Exchange Transfusion, with < 7 days old Rh D negative and ABO compatible with the baby and with the mother’s serum by cross-match. Normally 500 ml is sufficient for each transfusion.

- Phototherapy ( exposure of the infant to bright light of appropriate wavelength ) has been used to photodegrade the bilirubin to permit urinary excretion, thus reducing the likelihood of kernicterus.

- Management of Pregnant Women
Rh D negative women should have serum rechecked for antibodies in each trimester ( e.g, at initial presentation, 28 weeks and 36 weeks). If antibodies are detected, they should be identified and quantitated at regular intervals
( e.g 2 – 3 weekly, and more often in late pregnancy or if antibody levels are rising or high ).

- If the level of antibody is below 1.0 i.u. / ml ( 0.2 ?g / ml ), it require no action .
- A level of 10 i.u. / ml( 0.2 ug / ml ) usually reflects a seriously affected infant.
- Presence of bile pigment in the amniotic fluid shows severe haemolysis, the fetus can be kept alive by intrauterine transfusion of fresh blood after 24 weeks and premature delivery after 35 weeks.
- At birth prophylactic anti – D (Rh immunoglobulin) should be administered to Rh negative mother.

- Prevention of Rh immunization :
Anti D is now given to every Rh D – negative woman giving birth to Rh D – positive child providing the woman has not been previously sensitized. 
The routine dose is 500 i.u. intramuscularly ( I/M ) within 72 hours of delivery.

- A KLEIHAUER TEST may be performed to estimate the severity of the fetal – maternal bleed.
- Woman having abortion at under 20 weeks of pregnancy, 250 i.u. anti D is given, and in those,
- Having abortion after 20 weeks, the usual dose of 500 i.u. is given.

ABO HAEMOLYTIC DISEASE OF THE NEW BORN.
- In 20 % of births, a mother is ABO incompatible with the fetus.
- Group A and group B mothers usually have only IgM antibodies.
- The majority of the cases of ABO HDN are caused by “ Immune” IgG antibodies in group O mothers with a group A or group B fetus.
- 15 % of pregnancies involve a group O mother with a group A or group B fetus.
- Most mothers do not produce IgG anti A or B and very few babies have severe enough haemolytic disease to require treatment. Exchange transfusion is needed only in 1 / 3000 infants.
- In contrast to Rh D HDN the ABO disease may be found in the first pregnancy and may or may not effect subsequent pregnancies.
- Direct antiglobulin test ( DAT ) on the infant’s cell is negative or may be weakly positive.
- Examination of the blood film shows agglutination and spherocytosis, polychromasia and erythroblastosis.