Haemolytic disease of the newborn (HDN)

Question 1

HDN - overview + pathophys (part 1)

Answer 1

1. Def = when a maternal antibody response is mounted against fetal red cells; these IgG antibodies cross the placenta and cause fetal RBC destruction. The ensuing anaemia, if severe, precipitates fetal hydrops, which is often referred to as immune hydrops
2. More than 50 red cell antigens have been reported to cause HDN, but only anti-Rh(D), anti-Rh(c) and anti-Kell cause serious fetal problems. Other antibodies are common but usually only cause mild to moderate HDN
3. 85% of Caucasians are negative for Rh(D) antigen (termed Rhesus-negative). If a woman is Rh(D) negative and her partner is heterozygous, each fetus has a 50% chance of being Rh(D) positive (autosomal dominant inheritance)
4. During pregnancy, fetal cells may cross the placenta and enter the maternal circulation, exposing the mother to ‘foreign’ red cell antigens that the fetus has inherited from the father (most likely to occur at delivery [60% of pregnancies] but may also occur spontaneously during pregnancy and in association with threatened or complete miscarriage, after trauma, and after invasive procedures such as amniocentesis, CVS, ECV or abruptio placentae)
5. Exposure to foreign fetal red-cell antigens may result in the development of maternal antibodies -> IgG antibodies actively transferred from mother to fetus (initially slowly, then increases exponentially from 24 weeks until term)

Question 2

HDN - pathophys (part 2) + clinical manifestations

Answer 2

1. HDN occurs when the lifespan of infant’s RBC is shortened by the action of maternal antibodies
2. Antibody-coated red cells are removed from the circulation by the fetal liver and splen, leading to anaemia

Mild HDN
3. Fetus may be born without major clinical problems; may only need postnatal observation

Moderate to severe HDN

4. Neonates - may need phototherapy or exchange transfusion. May have hyperbilirubinaemia/jaundicebc in utero the mother cleared this RBC breakdown product, but the immature neonatal liver is unable to cope
5. Early onset of severe disease = may result in fetal anaemia in utero -> extramedullary erythropoeisis (enlarged liver and spleen), cardiac decompensation and hydrops fetalis (immune hydrops). If untreated, usually results in fetal death

Question 3

HDN - potential sensitising events for rhesus disease (5+3=8)

Answer 3

1. TOP or evacuation of retained products of conception (ERPC) after miscarriage
2. Ectopic pregnancy
3. Vaginal bleeding >12 weeks, or earlier if heavy
4. ECV
5. Blunt abdominal trauma
6. Invasive uterine procedure (e.g. amniocentesis or CVS)
7. Intrauterine death
8. Delivery

Question 4

HDN - ix/mx

Answer 4

1. All women should be checked for antibodies (rhesus and atypical) at booking - indirect antiglobulin test. If antibodies detected very early in pregnancy, should repeat after 20 weeks’ gestation
2. Once titre exceeds 1 in 16, ix are instituted to determine if fetus affected
3. Fetal Hb concentration may be measured by cordocentesis (fetal blood sampling from umbilical cord) - but this is invasive and associated with significant risk of fetal loss. Peak systolic flow in MCA reflects anaemia (faster flow = more anaemic fetus); if faster flow, cordocentesis indicated (?). Liver length, spleen perimeter and flow velocity changes in other fetal vessels have also been used to detect fetal anaemia
4. If cordocentesis confirms anaemia, an intrauterine transfusion can be performed
5. Intrauterine transfusions are usually stopped at around 34 weeks’ gestation and the fetus is delivered at 36-37 weeks. In less severe disease (where maternal blood titres do not rise >1/16), delivery is usually planned for after 37 weeks’ gestation

Question 5

HDN - prevention of Rhesus isoimmunisation

Answer 5

1. Principle of prevention = passive immunisation. Rh(D) negative women are given an injection of anti-D antibody at a time when it is likely that fetal cells may have entered the maternal circulation
2. The injected anti-D antibody binds to any Rh(D)-positive fetal cells present in the maternal circulation, allowing these cells to be rapidly cleared by the maternal liver and spleen before an immune response can take place
3. Anti-D is given to Rh(D)-negative women who have no pre-formed antibody in the following circumstances during pregnancy (3):
   a. Threatened or spontaneous miscarriage, invasive procedures, trauma, placental abruption (increased risk of FMH)
   b. Routinely at 28 and 34 weeks’ gestation
   c. Routinely at delivery if baby is Rh(D)-positive
4. Anti-D immunoglobulin should be given as close to the sensitising event as possible, and within 72h
5. The dose of anti-D given must be sufficient to remove all fetal cells from the maternal circulation. The Kleihauer-Betke test (which identifies fetal cells in maternal blood) is used to determine the volume of FMH and thus the dose of anti-D that should be administered after sensitising events