1. Dr. Sanjay Curpad. S

2. What is it?  A condition that has an adverse effect on the foetal red cells in response to the maternal immunization.

3. History  1609 First recognised by French midwife Louise Bourgeois  20 century Icterus gravis, erythroblastosis and hydrops as a continuum of same pathology  1939- Levine Steton identification of ABO blood group  1940 Lansteiner Rh group identified  1953 Chown identified pathophysiology and foetal maternal bleeding

4. Rhesus antigens Fischer and Race  3 pairs of antigens Cc,Dd,Ee  D is major cause of incompatibility  1945 Indirect coombs test  1950’s IgG & its Fc, Fab fragments  1965- identification of Pathophysiology  1969- Demonstration of Passive immunization

5. Pathophysiology 3 stages  Paternally derived antigen foreign to mother derived by foetus  Access of these red cells to maternal circulation to mount an immune response  Transplacental crossing of these antibodies to initiate destruction of foetal cells

6. Pathophysiology cont...  D antigen strongly immunogenic ( 50 times more than others)  Antibodies produced because of sensitization in pregnancy or transfusion  Multiple foeto-maternal bleed more likely to produce immunization than single dose

7. Factors influencing immune response Immunization risk if ABO compatable-16% Risk if ABO incompatible 1.5-2% Immunization depends on size of FMH 1ml FMH- %)% risk of immunization in ABO compatible women 0.1ml FMH -31% risk 1% women immunised by end of 3 rd trimester 16% risk of immunization after 1 st delivery

8.  cDE/cde more risk of immunising  Finally depends on immune response of mother  First child rarely affected in Rh incompatibility

9. Incidence Anti D prophylaxis reduces HDN to 1.3/100000 live births England & Wales 17% births to Rh neg women 59% are Rh Positive foetuses Postnatal antiD prophylaxis reduced frequency to 1 in 21000 births 500 foetus develop HDN with loss of 20 foetus before 28 weeks, 20-25 babies and 45 foetus affected

10. Prevention  Administration of anti D immunoglobulin dramatically reduces rate of alloimmunization  Administration within 72 hours of sensitising event reduces risk of immunization by 90%  All Rh neg women delivering Rh pos babies to undergo screen for quantity of FMH to determine additional dose required(British committee for standards in Haematology)

11. Prevention cont... Antenatal prophylaxis NICE - recommendations  AntiD 500 IU @28 & 34 weeks  1500 IU @ 28 weeks

12. Failure of prevention- reasons Primary reason - Failure to implement prophylaxis protocols- preventable cause  Failure to administer antenatal prophylaxis  Failure to recognise clinical events causing FMH  Failure of Postnatal immunoprophylaxis Second– spontaneous isoimmunization (0.1- 0.2%)

13. Preparations  Pooled sera- Risk of Infection ( west Nile fever, Creutzfeldt-Jokob disease etc)  Recombinant technology

14. Non Rh D alloimmunization  Antenatal screen detects clinically significant antibodies in 0.24-1% patients  Incidence of RhD isoimmunization decreasing hence more importance to other causes  43 other redcell antigens implicated  Other important causes antic, anti Kell, less so in anti E, anti C, anti k & anti Fy a

15. Non Rh D alloimmunization  Manitoba study anti c resulted in 2-7 fold greater incidence of non Anti RhD haemolytic disease  Study from Netherlands- 10% of cases involved anti K, 3.5% anti-c.

16. Anti Kell antibody 20 antigens Kell (K) & Cellano(k) are strongest immunogens 91% population Kell negative(kk) Development of immunization Previous transfusion (most common) Previous pregnancy (less common) Naturally ( rare)

17. Kell antibodies Cont...  Partners are likely to be Kell positive in 10%  Potential incompatibility in 5% ( because of heterozygosity)  2.5-10% of Kell immunised pregnancies deliver affected infants, half of them require intervention

18. Kell antibodies Cont...  Causes suppression of erythropoisis rather than red cell destruction  Not affected by previous obstetric history  Maternal Kell antibody titres – No co relation to severity

19. Management –Diagnosis if not previously affected  Obstetric history  Paternal Blood group  Prenatal diagnosis of Foetal Rh D status- 1997 Lo et.al  Maternal Serology Indirect IAT ( Coombs test)

20. Non-invasive fetal genotyping using maternal blood is now possible for D, C, c, E, e and K antigens performed in the first instance for the relevant antigen when maternal red cell antibodies are present. For other antigens, invasive testing (chorionic villus sampling [CVS] or amniocentesis) may be considered if fetal anaemia is a concern or if invasive testing is performed for another reason (e.g. karyotyping).

21. Referral to a fetal medicine specialist  when there are rising antibody levels/titres  level/titre above a specific threshold or ultrasound features suggestive of fetal anaemia

22. Previously affected baby  Maternal serum testing for titres  Percutaneous Umbilical blood sampling (PUBS)- Cordocentesis  Real-time Ultrasonography Peak MCA  Amniotic fluid spectrometry no longer used

23. Management anti Kell  Anti Kell titres – no co relation with severity  MCA dopplers helpful in detection of foetal anaemia

24. Referral to foetal medicine clinic  For antibodies other than anti-D, anti-c and anti-K  A history of previous significant HDFN  Intrauterine transfusion (IUT)  A titre of 32 or above, especially if the titre is rising as rising titres correlate with increasing risk and severity of anaemia.

25. MCA DOPPLERS

26. MCA – psv dopplers  Reference range for normal foetuses 0.86 to 1.16 times median  Moderate to severe anaemia if ≥ 1.5 times of median

27. Management  Titers ≤ 1:64 testing for titres every 4 weeks prior to 28 weeks and 2 weeks after 28 weeks  Titres > 1:64 referral to tertiary centre  Previous h/o Hydrops see at 14-16 weeks review  MCA dopplers start 18 week/ atleast fornightly

28.  Stable MCA below 1.29 MoM is reassuring. If antibodies are high, but stable and MCA persistently normal, foetal genotyping should be considered- Negative result will avoid further  When MCA peak systolic velocity reaches 1.5 MoM before 32 weeks - foetal blood sampling to detect foetal haemoglobin

29.  Delivery- high risk affected pregnancies 36-38 weeks  Low risk no evidence - ?38-40 weeks.

30. Management of mother For antibodies other than anti-D, anti-c, anti-C, anti-E or anti-K, maternity staff should liaise with their local transfusion laboratory to assess and plan for any possible transfusion requirements, as obtaining the relevant blood may take longer Pregnant women with red cell antibodies, who are assessed as being at high risk of requiring a blood transfusion, should have a cross-match sample taken at least every week.

31. Management of Mother Anti-D immunoglobulin should be given to RhD- negative women with non-anti-D antibodies for routine Antenatal prophylaxis, for potential antenatal sensitising events and postnatal prophylaxis. If immune anti-D is detected, prophylaxis is no longer necessary. Discussion and liaison with the transfusion laboratory are essential in determining whether anti-D antibodies are immune or passive in women who have previously received anti-D prophylaxis.

32. References  RCOG green top giuideline  Red cell immunization review Bidyut Kumar et-al  Review Diagnosis and management of non- anti-D red cell antibodies in pregnancy-K. Gajjar / C Spencer

33. Thank You