Hemolytic Disease of the Newborn

Hemolytic Disease of Hemolytic Disease of the Newbornthe Newborn

HDN - DefinitionHDN - Definition

• A condition in which the life span of A condition in which the life span of the fetal or newborn RBC is shortened the fetal or newborn RBC is shortened due to maternal Allo-antibodies due to maternal Allo-antibodies against paternal Antigens on fetal red against paternal Antigens on fetal red cells.cells.

• It was first reported by a french It was first reported by a french midwife in 1609 in a set of twins, but midwife in 1609 in a set of twins, but its pathogenesis not known until mid its pathogenesis not known until mid twentieth century. twentieth century.

Allo-antibodies Allo-antibodies implicatedimplicated

• Anti-DAnti-D• Anti-D+CAnti-D+C• Anti-D+EAnti-D+E

• Anti-CAnti-C• Anti-EAnti-E• Anti-cAnti-c• Anti-eAnti-e• Anti-K.Anti-K.• OthersOthers

Pathogenesis of HDN

• Feto-maternal Haemorrhage• Maternal Antibody• Placental passage of Antibody

from mother to fetus

• Attachment of maternal Antibody to fetal red cells

• Destruction of fetal red cells

Rhesus Hemolytic Disease Rhesus Hemolytic Disease of the Newbornof the Newborn

Factors effecting immunization & severity of

HDN• 1. Antigenic exposure :1. Antigenic exposure : Feto-maternal Hage occurs usually in late

pregnancy and delivery Amount is < 0.1 ml in 75% (Risk of sens. 3%) Amount is > 0.1 ml in 25% (Risk of sens.

22%) Amount is > 15 ml in 0.3% when mother is first sensitized this called

the primary response, while a repeat exposure to Ag in as little as 0.03 ml could induce the secondary response.


HDN• 2. Host factors :2. Host factors :

– Individual variability.– ~70% of RhD-ve will produce Anti-

D, if transfused RhD +ve blood.– ~10% of Rh D negative ladies will

not be immunized by an Rh D positive pregnancy.


HDN• 3. Immunoglobulin Class :3. Immunoglobulin Class :

– Only IgG passes the placenta.– Passage occurs starting at the 2nd

trimester and until birth.

• 4. Antibody specificity:


HDN• 5. ABO Group of the Mother :5. ABO Group of the Mother :

– Risk of immunization to D Antigen in ABO incompatible first pregnancies is ~ 3% , compared to 15% if ABO compatible.

• Why???Why???

Rhesus HDN• IgG antibody in mother passes to circulation

of Fetus• Destroy fetal RBC in spleen• Anemia• Stimulation of fetal marrow to produce RBC• Appearance of NRC in fetal blood

(erythroblastosis fetalis)• Both liver and spleen called in

(hepatosplenomegaly)• EMH leads to Portal hypertension & liver

damage lead to hypoproteinaemia.• Edema+effusion+Ascites• Hydropes fetalis.

When will hemolysis stops ?

• It will continue after birth, It will continue after birth, Why?Why?• Maternal antibodies are still Maternal antibodies are still

present in fetal circulation present in fetal circulation (half (half life 25 days)life 25 days)

• Bilirubin will accumulate beyond Bilirubin will accumulate beyond ability of liver to handle, ability of liver to handle, because of liver immaturity, because of liver immaturity, but but why will it be more apparent why will it be more apparent after birth??after birth??

Prediction of possible HDN

• Women at risk of alloimmunization Women at risk of alloimmunization should undergo indirect coomb’s test should undergo indirect coomb’s test and titres at their first prenatal visit.and titres at their first prenatal visit.

• If positive obtain a paternal blood If positive obtain a paternal blood type and genotypetype and genotype..

• If father is homozygous for Ag, then If father is homozygous for Ag, then do serial titres for antibody in mother.do serial titres for antibody in mother.

• If father heterozygous, then If father heterozygous, then determine fetal blood type by PCR, determine fetal blood type by PCR, by testing fetal cells in Amniotic fluid by testing fetal cells in Amniotic fluid or maternal circulation or by or maternal circulation or by performing cordocentesisperforming cordocentesis..

Prediction of possible HDN

• Indicators of severe HDN are :Indicators of severe HDN are :– Previous children with hemolytic

disease.– Rising maternal antibody titre.– Rising amniotic fluid bilirubin

concentration.– U/S evidence of Hydrops.

Clinically HDN presents Clinically HDN presents with :with :

• Jaundice, Pallor, hepatosplenomegaly, Hydrops in severe cases. The jaundice typically starts at birth or in first 24 hours and increased rapidly due usually to unconjugated bilirubin.

Severity varies :Severity varies :• Neonatal Hemolytic anemia.• Icterus gravidus Neonatorum• Intrauterine Death (Hydropes Fetalis).

• First child is classically spared , unless?!!!• Once immunized all future Rh(D) positives will

be affected.

Why does Hydrops occur in Why does Hydrops occur in HDN :HDN :

• Anemia is not the only cause.• Excessive hepatic extramedullary

hemopoiesis leads to portal and umbilical venous obstruction and diminished placental perfusion because of oedema.

• Increased placental weight and oedema of the chorionic villi interfer with placental transport.

• Hydrops results from fetal hypoxia, anemia, congestive heart failure, hypoproteinemia secondary to hepatic dysfunction.

• Hydrops does not occur unless Hb is <4 g/dl (PCV <15%).

Workup in HDN :

• Complete blood Picture shows :Complete blood Picture shows :– Anaemia.– Increased NRC (erythroblastosis

fetalis)– High retics counts.– Neutropenia maybe observed,

although after IUT neutrophilia is more likely.

– Thrombocytopenia : common after exchange or IUT.

Workup in HDN :

Metabolic abnormalities :Metabolic abnormalities :- Hypoglycemia is common.- Hyperkalemia and hypocalcemia are

common after exchange transfusion.

Serological tests :Serological tests :- In mother Indirect coomb’s positive.- In newborn direct coomb’s test is

positive.

Workup in HDN :

Imaging studies :Imaging studies :•High resolution US has great impact in detecting early hydrops.

•Also this US could be used to direct needles in fetal transfusion.

Rh Isoimmunization

• Prevention Prevention of Rh isoimmunizationof Rh isoimmunization::– Mainstay is Anti-D ImmunoglobulinAnti-D Immunoglobulin,

developed and used since the seventies.

• The main question is not whether women should receive such prophylaxis, but :– Which ones should do so..?– At what time they should do so?– And in what doses?

Prevention of Rh isoimmunizationPrevention of Rh isoimmunization

• Which women should do so..?– An Rh (D) negative women giving birth An Rh (D) negative women giving birth

to an Rh (D) positive fetus.to an Rh (D) positive fetus.– An Rh (D) negative woman having an An Rh (D) negative woman having an

abortion, chorionic villus biopsy, and abortion, chorionic villus biopsy, and external version of a breech external version of a breech presentationpresentation

– Consider it in those pregnant Rh(D) Consider it in those pregnant Rh(D) negative with abdominal trauma, negative with abdominal trauma, Placenta previa, abruptio Placenta previa, abruptio placenta,uterine bleeding from any placenta,uterine bleeding from any source.source.


At what time they should do so?At what time they should do so?– As soon as possible after birth of Rh As soon as possible after birth of Rh

D positive newborn, but up to 72 D positive newborn, but up to 72 hrs postpartum is acceptable.hrs postpartum is acceptable.

– Because of the presence of some Because of the presence of some risk of Rh isoimmunization during risk of Rh isoimmunization during pregnancy, though small (1.5%), pregnancy, though small (1.5%), Anti-D maybe given at 28-32 weeks Anti-D maybe given at 28-32 weeks gestation, in Rh D –ve mother.gestation, in Rh D –ve mother.


And in what doses?And in what doses?

Different experiences :Different experiences :In UK In UK : 100 µg (500IU): 100 µg (500IU)In Australia : In Australia : 125 µg125 µgIn US and some Parts of Europe: In US and some Parts of Europe: 200-300 µg (1000-1500 IU).200-300 µg (1000-1500 IU).

In principle In principle 20 µg (100IU)20 µg (100IU) of Anti-D is of Anti-D is sufficient to neutralize antigenecity of sufficient to neutralize antigenecity of

2 ml2 ml Rh D positive Rh D positive whole bloodwhole blood


– To Determine dose exactly we could do To Determine dose exactly we could do Kleihauer-Betke test, which is a test Kleihauer-Betke test, which is a test designed to determine the proportion of designed to determine the proportion of fetal cells in maternal blood (i.e.FM fetal cells in maternal blood (i.e.FM Hage)Hage)

– Because of the length taken in doing Because of the length taken in doing the above test, some physicians resort the above test, some physicians resort to Indirect Coomb’s test in the mother to Indirect Coomb’s test in the mother to assess the adequancy of Anti-D in a to assess the adequancy of Anti-D in a women with significant FMH; the test women with significant FMH; the test should become positive in a previously should become positive in a previously negative lady indicating the presence of negative lady indicating the presence of an excess antibody.an excess antibody.

Diagnosis of Rh Diagnosis of Rh isoimmunizationisoimmunization

• All pregnant women should have their Rh phenotype determined early in pregnancy.

• Women negative for D or other antigens in Rh system should be further screened for their antibodies.

• The presence of antibodies indicates that the fetus maybe affected.

Some important notes on Iso-immunization

• The Antibody titre does predict the The Antibody titre does predict the presence or severity of fetal disease, presence or severity of fetal disease, except in first affected pregnancy.except in first affected pregnancy.

• In subsequent pregnancies, the most In subsequent pregnancies, the most powerful predictor of severity , is its powerful predictor of severity , is its severity in previous pregnancies.severity in previous pregnancies.

• Rising serial antibody levels is Rising serial antibody levels is another important predictor of another important predictor of severity.severity.

Treatment of Iso-immunization

• Early delivery before the baby is too severely affected, remains the mainstay of established isoimmunization.

• IU transfusion should be considered, until the fetus is mature enough for delivery.

• Plasmapharesis to reduce antibody levels during pregnancy.

• IV IG with or without plasmapharesis .• Immunosuppression by promethazine!!!

What to do if you have a sensitized mother with detectable antibodies ??

• If titre is < 16, repeat at monthly intervals in 2nd trimester and biweekly in 3rd.

• If titre is > 32, repeat at 18-20 w if persistent or increasing, do amni ocentesis or umbilical blood sampling between 20-24 weeks.

• If however mother has severely affected previous children then aminocentesis is done earlier (18-20 wks).

What to do if you have a sensitized mother with detectable antibodies ??

• Aminocentesis :Aminocentesis : is basically used to determine the degree of fetal affection indirectly by assessing the bilirubin level by measuring the change in OD at 450 nm, then using liley graph to determine severity.

Zone III

Zone II

Zone I

Liley GraphLiley Graph

Severely affected : IUT/ Early delivery/ ET

moderately affected : IUT/ Early delivery/ ET

Not or mildly affected, repeat aminocentesis every 2-4 wks, to 34-36 wks

Management of sensitized Management of sensitized newbornnewborn

• InIn 50% the hemolytic disease is mild, with 50% the hemolytic disease is mild, with positive DATpositive DAT..

• Most have no anemia (HB>14 g/dl) and Most have no anemia (HB>14 g/dl) and minimal hemolysis (cord bilirubin < 4 minimal hemolysis (cord bilirubin < 4 mg/dl).mg/dl).

• They require early phototherapy, no They require early phototherapy, no transfusions.transfusions.

• Indication for Phototherapy are generally Indication for Phototherapy are generally based on Bilirubin level correlated with based on Bilirubin level correlated with age, so that it is indicated for age, so that it is indicated for

- - bilirubin >4 mg/dl at birth, and bili>10 if <12 bilirubin >4 mg/dl at birth, and bili>10 if <12 hrs, and bili>14 if less than 24hrs.hrs, and bili>14 if less than 24hrs.


• InIn 25% the hemolytic disease is moderate, 25% the hemolytic disease is moderate, with positive DATwith positive DAT..

• Most have ,moderate anemia, and although Most have ,moderate anemia, and although they may not be clinically jaundiced at birth they may not be clinically jaundiced at birth they rapidly become so in the first 24 hrs.they rapidly become so in the first 24 hrs.

• They are at risk of encephalopathy without They are at risk of encephalopathy without proper treatment.proper treatment.

• They require early exchange transfusions They require early exchange transfusions (O negative fresh) and intensive (O negative fresh) and intensive

phototherapy, phototherapy, • They require monitoring for delayed anemia They require monitoring for delayed anemia

with low retics at 6 wks of life.with low retics at 6 wks of life.


• Exchange Transfusion Aim :Exchange Transfusion Aim :

1.1. Remove bilirubin.Remove bilirubin.

2.2. Remove sensitized red cells.Remove sensitized red cells.

3.3. Remove incompatible antibodies.Remove incompatible antibodies.

4.4. Replacement of incompatible red Replacement of incompatible red cells by compatible ones.cells by compatible ones.

5.5. Suppression of fetal Suppression of fetal erythopoiesis.erythopoiesis.Indications for exchange :Indications for exchange : Severe Anaemia < 10 g/dl; marked Severe Anaemia < 10 g/dl; marked

hyperbilirubinaemia (related to weight, the less the weight, the less the cut-off hyperbilirubinaemia (related to weight, the less the weight, the less the cut-off bilirubin for ET, rapidly rising bilrubin despite adequate phototherapy)bilirubin for ET, rapidly rising bilrubin despite adequate phototherapy)


• InIn 25% the hemolytic disease is 25% the hemolytic disease is severe, who are either stillborn severe, who are either stillborn or have hydrops fetalis at birthor have hydrops fetalis at birth

• This consequence indicate the This consequence indicate the inadequacy of our maternal inadequacy of our maternal management scheme and maybe management scheme and maybe preventable.preventable.

ABO Hemolytic Disease ABO Hemolytic Disease of the Newbornof the Newborn

ABO HDNABO HDN

• ABO incompatibility between the ABO incompatibility between the mother and newborn infant can cause mother and newborn infant can cause HDN.HDN.

• In 20% of all births, there is In 20% of all births, there is incompatibility between the mother incompatibility between the mother and the fetusand the fetus..

• Maternal anti-A and Anti-B (of IgG Maternal anti-A and Anti-B (of IgG type) cross the placenta to attach and type) cross the placenta to attach and cause destruction of fetal RBC with cause destruction of fetal RBC with corresponding Antigens.corresponding Antigens.

ABO HDNABO HDN

• Hemolysis associated with ABO HDN is mainly limited to O mothers with A or B blood.

–Why?

• Hemolysis is ABO HDN is Hemolysis is ABO HDN is classically mildclassically mild

– Why?Why?

ABO HDNABO HDN

• The history of previous transfusions or The history of previous transfusions or pregnancy is unrelated to severity or pregnancy is unrelated to severity or occurrence of ABO HDNoccurrence of ABO HDN.

• Why?Why?

• ABO HDN may occur in first or ABO HDN may occur in first or subsequent pregnancies, but not subsequent pregnancies, but not necessarily all of them.necessarily all of them.

ABO HDNABO HDN

• What do you expect the clinical What do you expect the clinical picture to be?picture to be?– Most often the presentation is with Most often the presentation is with

jaundice within 12-48 hrs of birth with jaundice within 12-48 hrs of birth with mild anemiamild anemia.

– Hb maybe normal and increased bilirubin maybe mild (as seen in physiological Jaundice).

– Rarely there is severe HDN requiring Rarely there is severe HDN requiring exchange transfusion.exchange transfusion.

ABO HDNABO HDN

• What do you expect to find on blood What do you expect to find on blood picture?picture?•Mild anemia.•Spherocytes and microspherocytes.•Polychromasia.

• Direct Coomb’s Test :Direct Coomb’s Test :•Usually positive, but negative results does

not exclude a diagnosis.•The severity of the disease is independent of

the strength of DCT.•Direct Coomb’s maybe positive in absence of

anemia.

Comparison between ABO & RH Comparison between ABO & RH HDNHDN

CharacteristicCharacteristic ABO ABO RhRhFirst pregnancyFirst pregnancy Yes Yes RareRare

Antibody IgGAntibody IgG Yes (Anti-A,B)Yes (Anti-A,B) Yes (Anti-D,etc)Yes (Anti-D,etc)

Bilirubin at birthBilirubin at birth NormalNormal elevatedelevatedAnemia at birthAnemia at birth NoNo YesYes

PhototherapyPhototherapy YesYes YesYesExchangeTransfusioExchangeTransfusionn

RareRare commoncommon

IUTIUT nonenone sometimessometimes

spherocytesspherocytes yesyes rarerare

Making a Diagnosis of ABO Making a Diagnosis of ABO HDNHDN

• When a newborn develops anemia in When a newborn develops anemia in the first 12-48 hrs, then ABO HDN is the first 12-48 hrs, then ABO HDN is among the DD.among the DD.

• Direct Coomb’s test is the most Direct Coomb’s test is the most important diagnostic testimportant diagnostic test.

• “In all cases of ABO HDN requiring transfusion therapy Direct Coomb’s was positive”

Making a Diagnosis of ABO Making a Diagnosis of ABO HDNHDN

• On useful policy is to collect cord blood samples On useful policy is to collect cord blood samples by venipuncture from all delivered infants.by venipuncture from all delivered infants.

• If the infant will thereafter develop jaundice, then ABO, Rh and Direct Coomb’sABO, Rh and Direct Coomb’s should be done.

• It is estimated that 90% of ABO HDN 90% of ABO HDN complicated by Jaundice will have a positive complicated by Jaundice will have a positive Coomb’s.Coomb’s.

• If coomb’s is negativecoomb’s is negative, other cause of jaundice should be excluded.

• If all other possible cause excluded, then an eluate of the cord RBC will always reveal ABO antibodies in ABO HDN>

Other HDNs and Main DDOther HDNs and Main DD

• Anti-K• Any Immune IgG Blood system antibody

may theoratically be implicated.

• Other causes of Hemolysis in newborn are:– Hereditary Spherocytosis.Hereditary Spherocytosis.– G6PD deficiency (esp. in Iraq)G6PD deficiency (esp. in Iraq)

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Hemolytic Disease of the Newborn