Summary BHCS3014 Haemolytic disease of the foetus and newborn
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Cours
BHCS3014 Reproductive Sciences (BHCS3014)
Établissement
Plymouth University (UOP)
Compiled from lecture notes, this is a condense but detailed summary of the topic of haemolytic disease of the foetus and newborn on the module BHCS3014. Containing an overview of all the content in a logical order, easy to search and use for revision.
Haemolytic disease of the foetus and newborn
• Human blood groups
o Blood group antigens cause blood group incompatibility
o Most important during transfusions and incompatible pregnancies
o Blood antigens are expressed as membrane proteins (e.g., Rh) or as glycoproteins that are
attached to membrane proteins/lipids (e.g., ABO)
o ABO is a carbohydrate system - An enzyme synthesises and adds different antigens to
different glycoproteins/lipids
o Rh proteins are transmembranous with the antigen expressed on an external loop
o There are 43 different blood groups systems – each confer a wide range of functions to red
blood cells
▪ Complement control
▪ Structural
▪ Carbohydrates (ABO)
▪ Transport (Rh)
▪ Surface enzyme
▪ Cytokine receptor
▪ Cell adhesion
o Only ABO and Rh are routinely tested for
• Rh blood group system
o First described by Landsteiner in 1940
o 2nd most significant after ABO group
o Major cause of HDFN
o RhD gene on chromosome 1
▪ 10 exons
▪ Rhesus boxes either side of gene
▪ Smp1 gene after (in between RhD and RhCE genes)
▪ RhD and RhCE genes are ‘tail-to-tail’ – 1 → 10; 10 → 1
▪ Arose as duplication from ancestral RhCE gene
o RhD positive = RhD antigens on erythrocytes
o RhD negative (Caucasian) = missing entire RhD gene
▪ Unequal crossing over of Rhesus boxes 15,000 years ago lead to gene being lost
o RhD negative (African) = RhD pseudogene
▪ All exons present
▪ 37bp duplication upstream of exon 4
▪ 3bp swaps in exon 5
▪ Stop codon in exon 6
▪ Gene (and therefore protein) is non-functional due to mutations
o RhD status of parents – HDFN arises from RhD incompatibility
Mum Dad % of RhD+ foetus
D- D- D- D- 0%
D- D- D+ D- 50%
D- D- D+ D+ 10%
• Haemolytic disease of the foetus and newborn
o RBCs of the foetus express Rh antigen (foetus is RhD+)
o Even though placenta stops mixing of baby and mother’s blood, leaking occurs or blood
contact at birth
o When RhD- mother has contact with Rh antigens, her immune system identifies them as
foreign, so response is elicited
, o Mother’s IR produces anti-Rh IgM and memory cells – as IgM cannot pass through placenta,
1st pregnancy is safe
o Problems occurs with 2nd pregnancy if mother sense Rh antigens again – memory cells
produced IgG which can pass through placenta and attack foetal RBCs = erythroblastosis
fetalis and miscarriage risk
o RhD antigens most antigens to cause HDFN and is the only routinely tested for
• Foetal alloimmunisation
o Incompatible antigen must be expressed by foetus during pregnancy
o Blood group antigen is immunogenic
o Must be an alloimmunisation event – foetal blood is exposed to maternal immune system
• Anti-D prophylaxis reduced deaths – clinical management of HDFN
o Immunised RhD+ males used to generate anti-D antibodies
o Routine antenatal anti-D prophylaxis (RAADP) dropped mortality by 1000s+ (1950s) to 20-25
(1980s) per year
o Prevents mother’s IR to foetal Rh antigens
o Possible immune mechanisms
▪ Anti-D Igs binds RhD+ RBC and inhibits the cross-linking with ITAMs on B-cells, so no
B-cell activation and instead trigger FcyRII ITIM (B cell resting state) – most likely
▪ Anti-D Ig binding to D antigen masks antigen from B-cell (no activation) – unlikely as
would need lots of anti-D Igs
▪ Anti-D Ig tags RhD+ RBC for macrophage engulfment and clearing from Mother’s
system – not likely as macrophage engulfment would trigger IR
o Major of cases of D immunisation prevented by administration of anti-D post-partum or
post-abortion
o 1-2% of D- women with D+ infants will develop anti-D Igs prior to delivery
o Antenatal administration of anti-D is very effective - endorsed programme providing RAADP
as either 2 doses or 1 dose
• Antenatal management of HDFN
o 12-week serology scan
▪ No anti-D Ig detected
• D- foetus = no further action
• D+ foetus – ultrasound for hydrops, MCA ultrasonography, intrauterine
transfusion (repeat if necessary)
o Antenatal prophylactic anti-D administered 28-32 weeks if mother has anti-D Igs or if baby is
D+
o Postpartum prophylaxis anti-D and FMH determination
• Feto-maternal traffic of immunoglobulins
o Maternal IgG must cross the placenta to reach the foetus
▪ Syncytiotrophoblasts
▪ Foetal capillary endothelial cells
o Neonatal Fc receptor (FcRN) mediates this process
o 2 stage transport
▪ IgG pinocytosised into acidic endosomes where IgG-FcRN complex forms with high
avidity
▪ IgG-FcRN complexes are shuffled to basolateral surface of endothelial cell and
released at a neutral pH (foetal circulation 7.4)
o IgG concentrations in the foetus are approx. 10-20% of maternal levels during first half of
pregnancy – rise to level of 15g/L at full term, reflecting the maturation of the IgG transport
system (maternal levels 13 g/L)
o Binding to FcRN allows transport to foetus, unbound IgG degraded by lysosome
o FcRN structure
▪ Heterodimer
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