HDFN Aetiology- amanda Flashcards
HDFN
Haemolytic disease of the fetus and newborn
When was the aetiology of HDFN finally understood?
1950
— newborns RBCs attacked by antibodies from the mother
- attacks begins while baby is still in the womb and is caused by an incompatibility between the mothers and baby’s blood
What is HDFN
Destruction of the RBCs of the fetus and neonate by antibodies produced by the mother
HDFN condition on lifespan of fetal or neonatal red cells
Lifespan of red cells shortened due to maternal allo-antibodies reacting against red cell antigens acquired from the father
What is HDFN or erythroblastosis fetalis due to ?
Presence of immature red cells in the foetal circulation
What stimulates antibody production in the mother?
Placenta is a barrier to cellular transfer however some of the infants blood may enter the maternal circulation during a fetomaternal haemorrhage
- this can cause the formation of antibodies against the fetal red blood cells
- if mother’s antibodies pass into circulation of subsequent foetuses they may destroy the foetal red blood cells, causing the severe haemolytic disease of newborns
Is first baby usually harmed by HDFN
NO-
HDFN and Rh
Same type of immune reaction occurs in blood of an Rh negative mother carrying an Rh positive foetus
-probability is high if father is Rh positive, some of infants blood may enter maternal circulation, causing formation of agglutinins against foetal red blood cells
HDFN and Rh part 2
- at birth mother may become exposed to Rh+ blood of foetus
- exposure to Rh antigen causes mother to produce anti-Rh antibodies
-antibodies can cross placenta but blood cells cannot
If mother becomes pregnant with a second child that is Rh+ then destruction of foetal blood can occur
True
Pathophysiology of HDFN- primary response
After initial exposure to foreign antigen, the maternal immune system produces IgM antibodies that do not cross placenta
HDFN- secondary response
Later, immunoglobulin class switching occurs and IgG antibodies are produced that can traverse placental barrier
- normally IgG anti-D antibody does not reach a significant level during first pregnancy to cause significant destruction of foetal red cells
-repeat exposure to same antigen during subsequent pregnancy rapidly induces further IgG production
What is most common cause of severe HDN
Rh
What determines proportion of foetal RBCs in maternal circulation?
Kleihauer-Betke acid elation technique
When is risk of HDN increased?
Pregnancies complicated by placental abruption, spontaneous or therapeutic abortion and toxaemia
What happens after sensitisation ?
Maternal IgG antibodies cross placenta, attach to specific antigen on foetal red cells, antibody coated RBCs lyse, prolonged haemolysis can lead to severe anaemia due to inability of haemopoietic system to compensate, heme released and converted into unconjugated bilirubin
Pathogenesis of HDFN
- Severe anaemia due to RBC destruction gives rise to tachycardia
-cardiac insufficiency and reduced alpha-fetoprotein due to compensatory extra medullary haemopoiesis in liver and reduced production of proteins
Cardiac insufficiency and reduced protein production leads to hypotension, oedema, and ascites - tissue oxygenation reduced to vital organs
-pleural effusion in space between lungs and ribs - ascites in peritoneal cavity
Clinical presentation of HDFN before birth
- anaemia (destruction of red cells)
- tachycardia, heart failure
- hydrops fetalis (ascites and pleural effusions)
- organ failure
- foetal death
Clinical presentation of HDFN after birth
- anaemia
- heart failure
- build up of bilirubin which can result in Kernicterus
-severe growth retardation
-neonatal death if clinical intervention not provided
Anti-D: aetiology of HDFN
- most common cause of severe HDFN
- due to RhD incompatibility between mother and foetus (mother RhD neg and foetus RhD pos)
- effects are severe, can cause foetal death
- prevalence of HDFN due to anti-D substantially decreased by prophylaxis
HDFN lab finding at birth
Mum: RhD-ve with high plasma levels anti-D
Cord blood:
- variable anaemia (Hb<16g/dl)
-reduced RBC count
-high reticulocytes and erythroblasts
- baby RhD+ve
-raised serum bilirubin
-spherocytes on the peripheral blood film
-anti-D detectable in babies plasma
-reduced total protein in placement
-Direct Antiglobulin Test positive (DAT+)
Direct antiglobulin test (DAT)
-test performed on red cells to determine whether cells have been coated with antibody in vivo
-utilises anti-human globulin reagent to detect the presence of antibodies bound to the surface of red cells
- cells can be DAT positive in:
— HDFN when maternal antibody has crossed the placenta and bound to incompatible foetal antigens most commonly RhD
—following incompatible transfusion when the transfused donor cells are sensitised with patients antibody
—if patient has an autoimmune condition and is producing antibodies to their own cells
Incidence of HDFN in UK
Pre 1969- 1% all newborns affected by HDFN, mortality rate of 46/100,000 births
NICE 2011- under 1% of RhD negative pregnant women sensitised , mortality of 1.6/100,000 births
Reduction occurred due to introduction of RhD prophylaxis in 1969
Antenatal prophylaxis
1953-chown confirmed pathogenesis of Rh alloimmunisation to be the result of passage of Rh+ve foetal RBC after transplacental haemorrhage
19666- Anti-D immunoglobulin prophylaxis (RhIgG prophylaxis) prevents sensitisation of Rh-ve women
1971- WHO makes recommendations as to dosage
What happens in antenatal anti-D prophylaxis ?
Foetal cells expressing RhD antigen of paternal origin are removed from maternal circulation by administration of donor anti-D prior to production of a maternal immune anti-D.
- product must be given within 72 hours of a potential sensitisation event
-dose of anti-D required depends on gestational age or extent of FMH as determined by Kleihauer Betke test
How does prophylactic anti-D reduce level of RhD sensitisation ?
-precise mechanism of immunosuppression is unclear
-important that speed of which cells are cleared is significant
-binding of Fc part of IgG to low affinity FcR receptors on the splenic macrophages is essential for accelerated clearance of RBCs from the circulation
- down regulation of antigen specific B cells through co-ligation of B cell receptors and inhibitory IgG Fc receptors
-destruction due to phagocytosis or extracellular cytotoxicity by macrophages
When is RhD prophylaxis offered?
-anti-D immunoglobulin by injection offered to every RhD negative woman giving birth to a RhD positive child
-during pregnancy an RhD negative can either receive RhD prophylaxis when the RhD status of her child is unknown or following cell free foetal DNA (cffDNA) typing to determine the RhD genotype of the foetus
- kleihauer testing estimates the severity of feto-maternal haemorrhage (FMH)
Estimation of the size of fetomaternal haemorrhage - Kleihauer test
-most commonly used
-Kleihauer test-Betke test is a blood test used during pregnancy to screen maternal blood for presence of foetal red blood cells
-screening tool with threshold of 5mls
-based on principle that foetal cells with high HbF are less susceptible to acid elution compared to adult cells containing HbA
-subsequent staining makes foetal cells appear rose-pink, while adult RBCs are only seen as ‘ghosts’
- a large number of cells are counted under microscope and a ratio of foetal to maternal cells generated
-calculation of foetal cells in maternal circulation based on Mollison’s formula
Estimation of size of foetomaternal haemorrhage- flow cytometry
Flow cytometry determines ratio of foetal to maternal cells, identification of foetal cells using fluorescent labelled antibodies to either RhD or HbF
-using fluorescently labelled anti-D to enumerate RhD positive foetal cells among RhD negative maternal cells
-recommended reference method, less widely available, can detect low bleed volumes accurately
WHO recommendation for prophylactic anti-D dosing
-less than 12 weeks gestation: no anti-D required
-less than 20 weeks gestation: standard dose of 250IU anti-D
-20-40 weeks: estimate level of prophylactic anti-D required using Kleihauer or Flow cytometry technique
Benefits of routine antenatal anti-D prophylaxis (RAADP)
-3% of pregnant women have FMH in 1st trimester, 12% in 2nd and 46% in 3rd.
-NICE recommends non-sensitised RhD negative women receive routine antenatal anti-D prophylaxis to prevent sensitisation to undetected bleeds
-RAADP in 3rd trimester can reduce sensitisation rate from 1% to 0.34%
-500IU anti-D dose given at 28 weeks and further dose at 32 weeks
Concerns with RAADP
-maternal:
—theoretical risk of transmission of vCJD and other infections
—spiritual, philosophical, religious objections
—questioning paternity of baby with all the testing
-establishment concerns:
—logistics of administration
—RhDIg resource
—unnecessary for RhD negative women carrying RhD negative foetus
