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Haemolytic Disease of the Fetus and Newborn

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1 Haemolytic Disease of the Fetus and Newborn
Chapter 11 Mollison 11th Edition- notes and embellishments Dr Debra Lane Medical Director Canadian Blood Services Winnipeg

2 First Case Levine and Stetson (1939) described a woman who bore a macerated fetus and then developed a transfusion reaction after a transfusion from her husband POSTULATED IT WAS PRODUCTS FROM THE FETUS

3 HDN-Definition Haemolytic Disease of Newborn is a condition in which the lifespan of the infants red cells is shortened by the action of mother’s antibodies which have crossed the placenta The disease starts in the fetus and should be renamed Hemolytic Disease of the Fetus

4 Sensitization RH (D) negative fetus may develop a positive DAT by the 8th week Severe death and anemia can occur by the 18th week The hemolytic process is maximal at birth and decreases with the diminution of the maternal antibody Jaundice increases after birth

5 +DAT≠ HDN Many infants with a positive DAT do not have increased red cell destruction Serum bilirubins rise in most infants first two to three days of life Hemoglobins fall for the first two months of life

6 Transfer of Antibodies
Only occurs via the placenta IgG only bound to FC receptor Specialized neonatal FC receptor (FcRn) Function depends on dimerization with β2 microglobulin Only occurs between mother and fetus It is an active process- only small amounts transferred early in pregnancy

7 IgG transfer This is slow initially
At term infants IgG may be higher than mothers Half life two to three weeks in the newborn DAT may remain positive for three months in non-treated infants

8 Most common Anti-A and Anti-B are the most common antibodies
ABO hemolytic disease is common, but not severe Anti-D used to be the most common antibody causing HDN Still the most common causing Fatal HDN

9 In England Wales fatal HDN:
Fatal anti-c and Kell 1977 4 1990 4

10 Immunogenicity D>c>K Most antibodies can cause HDN
Severe ones include RH, anti-K, -k, -Kpa, -Ku, -Jsa, -Jsb, -Jka, -Fya, -M, -U, -PP1Pk, -Dib, -LAN, LW, -FAR, -Good, -WRA, -Zd

11 Quantification of Fetal Cells
Number of fetal cells Number of Adult cells

12 Detection of Fetal Cells by Acid Elution
Described by Kleihauer and Betke Blood films are treated with acid buffer Counter-stained the fetal cells appear as red cells on a sea of white ghosts Normally 1 to 2% red cells are fetal In 25% of females the fetal hemoglobin rises during pregnancy and may reach 7%

13 Must remember Fetal cells are larger than adult cells
Not all fetal cells stain darkly by acid-elution Arbitrary figure for maternal cell volume has to be assumed

14 Assumptions Fetal red cells 22% bigger
92% of the red cell stain darkly Average red cell volume of recently delivered woman is 1800 mls The volume of fetal red cells in the maternal circulation is 2400/ ratio of darkly staining cells to regular cells

15 Estimating Transplacental Hemmorhage-Slides
Using slides is inaccurate Depends on the thickness of slides Skill of technologists

16 Rosetting Tests Used as a screen
Anti-D is added to red cells from the D neg mom which coats any D pos cells Red cells are washed D positive (enzyme treated) detector cells are added which form rosettes around the D positive cells in the original sample

17 Flow Cytometry Maternal sample treated with anti-D and then fluorescein-labelled anti-IgG Can detect 1/1000 Lack of consensus in studies comparing flow to BK may be a reflection of technical differences. Need standardization of flow Gating of red cells Not universally accessible

18 Fetal Cell detection in Third Trimester
Authors 28-30 weeks 30-39 weeks Bowman and Pollock 0.40% 1.84% Huchet et al 5.8% 7.0%

19 Trans Placental Hemorrhage (TPH) with Amniocentesis
1981 to 1984 of 1000 women with amniocentesis for genetic disorders, 2.6% had TPH >0.1 ml 1.6% > 1.0 ml

20 TPH with Amniocentesis
Bowman and Pollock 1200 having amniocentesis for HDN 2.3% TPH >0.1 ml 1.8% TPH > 1.0 ml

21 Chorionic Villus Biopsy
Done at 7 to 10 weeks No fetal cells were detected But αfetoprotein increases- so Rh Immune globulin is recommended

22 Normal Delivery 1.0% have 3.0 ml or more 0.3% have 10 mls or more
When there is ABO incompatibility between the fetus and mom, less fetal cells are found in circulation Caesarean section and manual removal of placenta give a considerable increase in fetal cells

23 Clinical manifestations of HDN
Rapid jaundice If not treated may develop kernicterus with: Lethargy Spasticity Opisthotonos

24 Kernicterus Rare under 306μmol/L Non-immunologic hydrops 1/3500 births
Cardiac Genetic Twin to twin transfusion

25 Anti-D Develops late in first pregnancies- 28 weeks
First child rarely affected Stillbirth rate 6% with second pregnancy 29% with third

26 Prenatal testing All D negative women should be tested at the first antenatal visit and at 28 weeks Anti-D at first trimester due to previous transfusion or undiagnosed or undisclosed abortion

27 New anti-D in Second Pregnancy
Due to missed anti-D Anti-D given too late or insufficient dose

28 PCR for Prenatal Determination of “D” Status
PCR amplification of fetal DNA for RHD Uses fetal DNA present in the maternal sample No risk of TPH No possibility of sensitizing the mother RHD is absent in D negatives- in whites Pseudo RHD in blacks

29 Real time PCR Read Mollison

30 Antenatal Assessment Used to include fetal blood sampling

31 Amniocentesis Estimating the amount of bile pigment in amniotic fluid is performed by measuring the optical density at 450 nm between the observed density and an extrapolated baseline Amount falls with pregnancy so the age of the fetus must be considered

32 Liley (1961) Developed charts to determine the severity from 27 weeks onward They cannot be used prior to 27 weeks Liley had three zones indicating the approximate severity of HDN

33 Comparison of Liley {Delta}A450 values with bilirubin concentrations measured with the standard (A) and modified (B) iterative methods, and log-linear chart (C), extrapolated to 17 weeks of gestation, showing the three risk zones described by Liley Egberts, J. et al. Clin Chem 2002;48: Copyright ©2002 American Association for Clinical Chemistry

34 Examination of the Fetus by Ultrasongraphy and fetal Doppler blood flow
Can be used to diagnose hydrops fetalis Ascites Pleural effusions Pericardial effusions Skin edema (Bowman 1983)

35 Ultrasonography Can detect small pericardial effusions
Dilated cardiac chambers

36 Fetal Doppler Reported 2006 NEJM Oepkes et all 355(2) 156
Prospective International Trial of woman with anti-D, anti-c, anti-E,and anti-FYa With a titre of 1/64 165 fetus 74 with anemia


38 Comparison Fetal Doppler versus Amniotic Fluid
Sensitivity 88 % 76% Specificity 82% 77% Accuracy 85%

39 Fetal Blood Sampling Ultrasound guidance with a needle into the fetal umbilical or hepatic vein 394 woman with 606 samplings the fetal loss was 0.8% Fetal MCV 118 to 135 Betke- Kleihauer Fetal hemoglobin determined prior to fetal transfusion

40 Assessment of Severity of HDN in Newborn
Cord blood gives the most reliable hemoglobin 13.6 to 19.6 Range is wider for first day of life

41 Methods of Treatment Plasma exchange in the mother IVIG to mom
IVIG to fetus Transfusion of the fetus in-utero Post –natal exchange transfusion Phototherapy to reduce serum bilirubin

42 IVIG to mom/baby IVIG 2g/kg over 5 days
Weekly injections of 1g/kg +/- plasma exchange Might act by saturating the fetal FcRn and inhibiting placental transfer A small series was done transfusing fetuses with IVIG mean dose 85.7mg/kg/body weight No benefit- Dooren et al 1994

43 Transfusion of the Fetus in Utero
1963 Liley used intra-peritoneal transfusion Taken into the bloodstream via the sub-diaphragmatic lacunae and right lymphatic duct Uptake depends on diagphragmatic movements Easy to perform Can be done in conjunction with intravascular transfusion Cannot be done in infants without diaphragm movement

44 Intravascular Transfusion
Needle into the umbilical vein with ultra sonic guidance Excellent results by Bowman 1990 16/22 hydropic fetuses survived 3/6 deaths were between weeks in fetuses of iv drug abusers Rodeck 1984 infants weeks 25/29 with RH D HDN survived ( 10 hydropic)

45 Requirements for Exchange Transfusion blood
UK uses blood less than 72 hours In Manitoba less than 5 days or we wash the units The supranatant is removed and replaced with AB plasma St Justines uses albumin- reduces donor exposures O negtive, K negative and compatible with mothers antibody ( c negative if required) PCV 0.70 to 0.85 Irradiated CMV negative

46 Transfusion volume 50/ml /kg estimated non-hydropic weight
30-40ml/kg estimated non-hydropic weight for hydropic fetuses (Bowman 1994) Red cells suspended in non-protein solutions such as SAG-M or Adsol should not be used for transfusion to the fetus in-utero. ( In Mollison no reference)

47 Alloimummization of the Mother
May occur with fetal transfusion Fetal cells may be shed into the peritoneum May enter maternal vessels on placenta I had one mother develop three new antibodies Donor red cells are less frequently the source of immunization than fetal cells

48 Exchange Transfusion- Postnatal
Diamond 1947 introduced the method Blood is withdrawn and injected, intermittently through a catheter Passed up umbilical vein Primary objective- remove D pos rbcs Secondary- remove bilirubin Clinicians like to exchange relatively large amounts of blood( 200 ml/kg)

49 Blood requirements Plasma reduced Less than 7 days
Rh and Kell neg/ compatible with mom PCV 0.60 Screened for anti-HBS CMV neg Mollison does not say irradiated- we irradiate.

50 Indications for Exchange Transfusion
When fetus is exchange prenatally they usually do not need exchanges just booster transfusions 80% okay with phototherapy Exchange if bilirubin threatens to exceed 340umol/L Hg should be checked every 10 days if Hg, 70g/L 20ml/kg given- Bowman

51 Exchange continued Not transfused prenatally- cord Hg, 110g/L is an indication for exchange

52 Phototherapy Light at 420-480nm bilirubin converts to biliverdin
First reported Cremer et al 1958 Tabb 1972 (controlled trial) Some have combined phototherapy with IVIG and have avoided exchange 11/16 only phototherapy needed exchange 2/16 needed exchange with both (Rubo and Wahn 1991)

53 Kell HDN Very sever at any titre 1/1000 pregnancies
History of transfusion in 88% 1/40,000 Bowman 1994 Fetal anemia is due to the suppression of erythropoiesis Kell antigens are present on early erythroblasts

54 Kell HDN Poor correlation with severity of the disease and the mother’s titre Women with anti-K should be sent to Fetal assessment immediately and not wait for a rise in titre Bowman (1989) saw a hydrops at 23 with a anti-Kell of 8

55 Anti-k HDN Very rare May also be sever despite low titre
Anti-k (cellano) anti-k 16 The hemoglobin was 60g/L at 31 weeks Bowman 1989

56 Anti-c HDN Titre of 1:32 or greater identified all affected fetuses
32/49 deaths from HDN to 1990 in Wales 0.7/1000 pregnancies 40 to 50% immunized by transfusion Fetus relatively often c negative Antibody is of low titre

57 Anti-c Only 20% of c positive infants required exchange transfusion
(Astrup and Kornstad 1977) C typing of fetal DNS Polymorphism at nucleotide 307 of RHCE Quantitative real time PCR can be used for c typing of cell-free DNS from maternal blood in pregnancies at risk (Finning 2004)

58 Anti-E Most common after anti-D Often naturally occurring
Seldom causes HDN See more with Galileo Review 1959 to 2004 one perinatal death due to anti-E alone (Joy)

59 Anti-e Very rare Disease usually mild

60 Anti-Fya Mild hemolytic disease
At titres of .1/64 they should be closely monitored

61 Anti-Jkb Rarely causes sever HDN Single case of hydrops

62 Anti-M May fail to affect the fetus Rare cases of hydrops-two cases

63 ABO hemolyti disease Only two cases of hydrops due to ABO
Main need for exchange is to treat hyperbilirubinemia Moderate bilirubinemia controlled by phototherapy

64 I could go on forever- but this is it for today.

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