Haemolytic Disease Of The Newborn

Dr. Suhair Abbas Ahmed

Dept of Haematology

Hemolytic disease of the new born and fetus (HDN)

• It is a condition in which the life span of the fetal/neonatal red cells is shortened due to maternal allo-antibodies against red cell antigens inherited from the father.

• 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 lead to their destruction by the fetal reticuloendothelial system.

HDN

• ABO-HDN most commonly due to anti A produced by group O mother against a group A fetus. (The most common type of HDN but usually mild)

• Rhesus HDN caused by anti D, anti c, and anti E.

• Occasional cases of HDN are caused by antibodies of other blood group systems, anti Kell, anti Duffy, anti Kidd.

Rhesus HDN

Rhesus HDN

• When an Rh D-negative (rr or cde/cde) woman has a pregnancy with an Rh D-positive fetus, D-positive red cells cross the maternal circulation (usually during labour) and sensitize the mother to form anti D.

• Sensitization is more if the mother and the fetus are ABO compatible. WHY??

• The mother could have been sensitized previously by a previous miscarriage, amniocentesis or other trauma to the placenta or by blood transfusion.

• Anti D will cross the placenta to the fetus during the next pregnancy with an Rh D-positive fetus.

• Anti D antibodies will coat the fetal red cells and result in RES destruction of these cells leading to anaemia and jaundice.

Maternal IgG attack the Rh Ag on fetal cells

Destruction by RES

Anemia

Stimulate BM production of immature erythroblast

Erythroblastosis fetalis

Reduced hepatocellular production of plasma proteins

High output cardiac failure with generalized edema, effusion,

ascitis

hypoproteinemia

Extramedullary hemopoiesis

Hydrops fetalisPortal hypertension + hepatocellular damage

Hepatosplenomegaly

Pathogenesis of HDN

Pathogenesis of HDN before and after birth

Neonatalliver is immature and

unable to handle bilirubin

Coated red blood cellsare hemolysed in

spleen

Unconjugatedbilirubin

Conjugatedbilirubin

Clinical features of HDN

• Severe disease: intrauterine fetal death from hydrops fetalis.

• The baby looks oedematous, with ascites• The placenta is bulky swollen and friable• Pathophysiology

– Extravascular hemolysis with extramedullary erythropoiesis

– Hepatic and cardiac failure

Hydrops fetalis

• Moderate disease: the baby is born with severe anaemia and jaundice and may show pallor, tachycardia, oedema and hepatosplenomegaly.

• Unconjugated bilirubin can deposit in the basal ganglia and may lead to kernicterus (CNS damage with generalised spasticity and possible subsequent mental deficiency, deafness and epilepsy).

• Mild disease; mild anaemia with or without jaundice.

Laboratory Findings at Birth

• Cord blood: • variable anaemia ( normal level of Hb13.6-19.6

g/dl)• High reticulocyte count• Baby Rh D positive• Direct antiglobulin test is positive• Serum bilirubin is raised • Many erythroblasts are seen in the blood film in

moderate and severe cases (erythroblastosis fetalis).

P

N

Blood film of a fetus affected by Rh HDN showing polychromasia (P)and increased number of normaoblasts (N)

Direct antiglobulin test

Red blood cells from the baby

Antihuman globulin reagent added

agglutination= positive reaction

Lab findings

• Testing the mother

• Rh D negative

• Indirect antiglobulin test positive indicating the presence of high plasma level of anti-D.

Indirect anti-human globulin test : The mother’s plasma is tested for the presence of antibodies.

The plasma is incubated with known red cells to give time for the antibodies toreact with the red cells. Then the AHG reagent is added, if agglutination occurs it means

that the test is positive,

Treatment

• Depends on the severity of the disease

• Exchange transfusion

• Phototherapy

Treatment

• Exchange transfusion is indicated if:• Clinical features: obvious pallor, jaundice, and

signs of heart failure• Laboratory findings: Hb<12.0 g/dl (cord blood)

with a positive DAT• A cord serum bilirubin> 60umol/l or infant

S.bilirubin>300umol/l • Bilirubin rising rapidly and positive DAT.• Premature babies are more liable to kernicterus

so exchange should be done if bilirubin is >200

Exchange Transfusion

• Exchange transfusion will help to replace the infant red cells and reduce the rate of bilirubin rise.

• Blood for exchange transfusion should be • < 7 days old• Rh D negative• ABO compatible with the baby and with the

mother’s serum by cross-match.• Around 500ml is sufficient for each exchange.

Phototherapy

• It is exposure of the baby to bright light of appropriate wave length.

• This method of treatment has been used to photodegrade the bilirubin to permit urinary excretion, thus reducing the likelihood of kernicterus.

Antenatal assessment of maternal blood

• The ABO, Rh groups and antibody screen should be performed in all pregnant women at booking (usually around 16 weeks’ gestation).

All women should have the testing repeated once more at about 28 weeks to confirm the Rh group and to detect the presence of atypical antibodies.

If the mother is unsensitized

• If the mother is RhD negative with no anti – D (unsensitized) by 28 weeks, routine antenatal prophylaxis anti – RhD immunoglobulin should be given.

• Following delivery, all RhD - negative women

who are unsensitized for RhD should be given prophylactic anti – RhD immunoglobulin if the infant is RhD positive

Mechanism of action of anti – RhD immunoglobulin

Administered antibodies will bind the fetal Rh- positive cells

Spleen captures these cells by Fc-receptors

Spleen removes anti-D coated red cells prior to contact with antigen presenting cells

If the mother is already sensitized

• The level of anti – D (antibody titre) in the mother’s serum correlates approximately with the clinical severity of the HDN.

Antibody titre

• Antibody titre should be monitored monthly to 28 weeks and 2 - weekly thereafter.

• levels < 4.0 IU/mL require no action, • a level > 4 -10 IU/mL indicates moderate

risk• 10 – 20 IU/mL indicates high risk of HDN • and levels greater than 20 IU/mL indicate

a high risk of hydrops.

How to assess the severity of haemolysis?

• The severity of the haemolytic process may be assessed by clinical and ultrasound monitoring, including Doppler flow velocity. The systolic velocity of the fetal middle cerebral artery is a reliable indicator of fetal anaemia.

How to assess the severity of haemolysis?

• Measurement of bile pigments in the amniotic fluid by spectrophotometry from week 28 onwards is another method.

• The absorbance of normal amniotic fluid over the range of wavelengths 400 – 600 nm forms a smooth curve when plotted on semi - logarithmic graph paper. (Liley graph)

• When there is an excess of bilirubin, the curve shows a greatly increased absorbance, with a peak at about 450 nm.

Liley graph

• Increasing OD as pregnancy proceeds indicates worsening fetal hemolytic disease.

• Zone III – severely affected

• Zone II – moderately affected

• Zone I – unaffected or mildly affected

Fetal management

• For severely affected fetus, ultrasound - guided fetal blood sampling from 18 – 20 weeks onwards can be performed.

• The fetal haemoglobin is measured and, if necessary, an intravascular transfusion with fresh ( < 5 days old) group O, RhD - negative, CMV - negative, irradiated blood of the desired packed cell volume (PCV) can be administered (Intrauterine transfusion).

Fetal management

• It is possible to determine the Rh genotype of the fetus from amniotic cells through DNA typing, thus avoiding further manipulations when the fetus is RhD negative.

• Fetal RhD genotyping is now possible by DNA extraction from maternal plasma from 16 – 18 weeks’ gestation; this non - invasive technique is replacing amniocyte typing.

ABO haemolytic disease of the newborn

• ABO HDN is usually restricted to group O mothers possessing IgG anti - A,B, in addition to IgM antibodies.

• The incidence of ABO HDN requiring treatment is extremely low.

ABO haemolytic disease of the newborn

• The lack of severity of ABO HDN is due to

the widespread occurrence of A and B antigens, not only on red cells but also in plasma and on other cells, which will partially neutralize maternally derived ABO antibodies.

• Furthermore, the A and B antigens are not fully developed in the infant and the number of ABO sites is much smaller than in adults

ABO haemolytic disease of the newborn

• In contrast to Rh HDN, ABO disease may be found in the first pregnancy and may or may not affect subsequent pregnancies.

• DAT on the infant’s cells may be negative or weakly positive.

• Blood film shows spherocytosis (not seen with Rh HDN), reticulocytosis, polychromasia and increased numbers of nucleated red cells.

Treatment

• Severe anaemia is uncommon.

• Hyperbilirubinaemia is more often a problem and often subsides with phototherapy, but may occasionally be serious enough to warrant exchange transfusion to prevent brain damage.

• Group O donor blood with low – titre anti - A,B should be used.

Haemolytic disease of the newborn due toother antibodies

• Other antibodies encountered as a cause of HDN are • anti – Kell, • anti Duffy,• anti Kidd• This usually occurs due to previous maternal blood

transfusions. • The disease is generally less severe than Rh HDN, but

may sometimes be serious enough to warrant early delivery and/or exchange transfusion, and occasionally requires treatment of the fetus.