Rh Disease

1. Rh Disease Sokołowska Małgorzata PAm Szczecin

2. Isoimmunization: • Isoimmunization: refers to the development of antibodies to red blood cell antigens folowing exposure to such antigens from another individual . • In the pregnancy the ,,other individual’’ is the foetus, 50%of whose genetic makeup is derived from the father

3. Isoimmunization: • If the mother is exposed to fetal red cells during pregnancy or et delivery, she may develop antibodies to fetal cell antigens.

4. Isoimmunization: • Later in that pregnancy or more commonly with the subsequent pregnancy , the antibodes can cross the placenta and hemolyze fetal red cells, leading to fetal anemia.

5. Isoimmunization: • Isoimmunization: can involve many of the several hundred blood group system. • This disorder is frequently reffered to as Rh isoimmunization, becouse the Rhesus (Rh) system is most frequently involved • Isoimmunization does develop with many other blood systems such as Kell,Duffy,Kidd,Lewis,Lutheran,Public antigens & Private antigens, Diego, and others

6. The Basics Of Blood Antigens: - • Appearance by 40 days of I.U. Life- unchanged till death. • Controlled by genes at unknown No. of chromosomal loci. • Also present in tissues & tissue fluids. • Blood group system: A group of antigens controlled by a locus having a variable no of allele genes.

7. The Basics Of Blood Antigens: - • > 15 blood group systems are recognised : • ABO, Rh, Kell, Duffy, MN, P, Lewis, Lutheran, Xg, Li, Yt, Dombrock, Colton, Public antigens & Private antigens. • Blood type- means individual antigen phenotype which is the serological expression of the inherited genes • Most of these blood group antigens have been found to be associated with hemolytic disease. • However– ABO & Rh account for 98%

8. CDE (Rhesus) Blood group system • This system includes five red cell protein or antigens : c, C,D,e,E. • No ,,d ,, antigen has been identified ,and Rh – or D – negativity is defined as the absence of the D - antigen. • The CDE antigens are of considerable clinical importance because most D-negative individuals become immunized after a single exposure

9. CDE (Rhesus) Blood group system • The CDE genes are located on the short arm of chromosome 1 and are inherited as a group, independent of other blood group genes. • Like many genes , their incidence varies according to racial origin (Native Americans ,Inuits, ,Chineseand other Asiatic peoples are almost all D-positive; Basques show the highest incidence of D-negativity

10. CDE (Rhesus) Blood group system • The C,c,E,and e-antigens have lower immunogenicity than D-antigen, but they can cause erythroblastosis fetalis • All pregnant women should be tested routinely for the presence or absence of D –antigen on their erythrocytes and for irregular antibodes in their serum.

11. Rhesus incompatibility • The rhesus system is more commonly associated with severe hemolytic disease. Of all the antibodies (C,D,and E), the D antigen is associated most commonly with severe hemolytic fetal disease, however, this can only occur if the mother is D-rhesus –negative and the baby is D rhesus –positive. Both anti- C and anti –E antibodies may also be associated with hemolytic disease requiring intrauterine fetal blood transfusion,but are much less commonly implicated.

12. Why Does Rh Status Matter?

18. Pathophysiology cont… Initial IgM followed by IgG in 2 wks- 6 mths Memory B lymphocytes activate immune response in subsequent pregnancy IgG Ab cross placenta and attach to fetal RBC’s Cells then sequestered by macrophages in fetal spleen where they get hemolyzed Fetal anemia

21. General Screening ABO & Rh Ab @ 1st prenatal visit @ 28 weeks Postpartum Antepartum bleeding and before giving any immune globulin Neonatal bloods ABO, Rh, DAT

22. Gold Standard Test Indirect Coombs: -mix Rh(D)+ cells with maternal serum -anti-Rh(D) Ab will adhere -RBC’s then washed & suspended in Coombs serum (antihuman globulin) -RBC’s coated with Ab will be agglutinated Direct Coombs: -mix infant’s RBC’s with Coombs serum -maternal Ab present if cells agglutinate

23. + Rh(D) Antibody Screen Serial antibody titres q2-4 weeks If titre ≥1:32 - amniocentesis or MCA dopplers and more frequent titres (q1-2 wk) Critical titre – sign risk hydrops U/S for dating and monitoring Correct dates needed for determining appropriate bili levels (delta OD450)

24. U/S Parameters Non Reliable Parameters: Placental thickness Umbilical vein diameter Hepatic size Splenic size Polyhydramnios Visualization of walls of fetal bowel from small amounts intraabdominal fluid may be 1st sign of impending hydrops U/S reliable for hydrops (ascites, pleural effusions, skin edema) – Hgb < 70

25. Amniocentesis Critical titre/previous affected infant Avoid transplacental needle passage Bilirubin correlates with fetal hemolysis ∆ optical density of amniotic fluid @ 450nm on spectral absorption curve Data plotted on Liley curve

27. Liley Curve Zone I – fetus very low risk of severe fetal anemia Zone II – mild to moderate fetal hemolysis Zone III – severe fetal anemia with high probability of fetal death 7-10 days Liley good after 27 weeks 98% sensitive for detecting anemia in upper zone 2/ zone 3

28. Middle Cerebral Artery Dopplers Measures peak velocity of blood flow Anemic fetus preserves O2 delivery to brain by increasing flow Sensitivity of detecting severe anemia when MCA >1.5 MoM approaches 100% Not reliable > 35 weeks GA

29. Fetus at Risk Fetal anemia diagnosed by: amniocentesis cordocentesis ultrasound hydrops middle cerebral artery Doppler Treatment: intravascular fetal transfusion preterm birth

31. Pathogenesis Of Rh Iso-immunisation Rh Negative Women Man Rh positive (Homo/Hetero)   Rh Neg Fetus No problem   Fetus     Rh positive Fetus  Rh+ve R.B.C.s enter Maternal circulation Mother previously sensitized Secondary immune response     Non sensitized Mother Primary immune response ? Iso-antibody (IgG)     ?    Fetus Fetus  unaffected, 1st Baby usually escapes. Mother gets sensitised?   Haemolysis 

32. Pathology Of Iso-immunisation AFTER BIRTH  HAEMOLYSIS  IN UTERO    Jaundice Kernicterus Hepatic Failure ANAEMIA BILLIRUBIN    HEPATIC ERYTHROPOESIS & DYSFUNCTION MAT. LIV NO EFFECT   DEATH IUD       PORTAL & UMBILICAL VEIN HYPERTNSION, HEART FAILURE ERYTHROBLASTOSIS FETALIS         BIRTH OF AN AFFECTED INFANT - Wide spectrum of presentations. Rapid deterioration of the infant after birth. May contiune for few days to few months. Chance of delayed anaemia at 6-8 weeks probably due to persistance of anti Rh antibodies.

33. The aetiology of rhesus disease: • Rhesus disease does not affect a first pregnancy • It requires that mother has had exposure to D rhesus - positive fetal cells in previous pregnancy and then developed an immune response that has lain dormant until a following pregnancy of a D rhesus-positive baby. • In the subsequent pregnancy , when maternal resensitization occurs ( rhesus- positive red cells pass from the baby to the maternal circulation),IgG antibodies cross from the mother to the fetal circulation. • If these antibodies are present in sufficient quantities fetal hemolysis may occur leading to such severe anaemia that the fetus may die unless a transfusion is performed.

34. Causes of Rh isoimmunization • Fetus must have Rh-positive erythrocytes, mother must have Rh negative • Sufficient number of erythrocytes must gain access to maternal circulation • Mother must have immunogenic capacity to produce antibody

35. Fetomaternal hemorrhage • Isoimmunization seems to be dose related • After transfer of .1 ml, 3% will be isoimmunized • 16% will be isoimmunized after first pregnancy if untreated • Without treatment eventually 50% will become sensitized • Can occur during pregnancy but rarely before 3rd trimester

36. Fetomaternal hemorrhage • Can occur following abortion and tubal pregnancy • More common following late terminatiion • Amniocentesis associated with significant hemmorage and isoimmunization

37. Pathology Of Iso-immunisation AFTER BIRTH  HAEMOLYSIS  IN UTERO    Jaundice Kernicterus Hepatic Failure ANAEMIA BILLIRUBIN    HEPATIC ERYTHROPOESIS & DYSFUNCTION MAT. LIV NO EFFECT   DEATH IUD       PORTAL & UMBILICAL VEIN HYPERTNSION, HEART FAILURE ERYTHROBLASTOSIS FETALIS         BIRTH OF AN AFFECTED INFANT - Wide spectrum of presentations. Rapid deterioration of the infant after birth. May contiune for few days to few months. Chance of delayed anaemia at 6-8 weeks probably due to persistance of anti Rh antibodies.

38. Management of Unsensitised Pregnancy • In Abortion, Ectopic, Amniocentesis, Chorionic villus sampling • Pregnancy < 12 weeks- 50mcg Anti D • Pregnancy >12 weeks- 150 mcg Anti D • Normal labour , cordocentesis : - 150 mcg Anti D • S. C. , abnormal labour with mannual extraction of placenta, IUD : 300ug Anti D • until 72 hours in one dose im. ( twins double doses) • - At birth- cord blood for ABO & Rh typing • Baby Rh negative – Be happy

39. Management of Sensitized Pregnancy • Careful planning during antepartum, intrapartum & neonatal period • Father’s blood type & Rh antigen status • Knowledge of maternal antibody titer to the specific antigen • Intrauterine foetal monitoring with repeated ultrasound examination, cordocetesis / amniocentesis

40. Features of fetal anaemia: • Note: clinical and ultrasound features of fetal anaemia do not usually become evident unless fetal haemoglobin is >5g/dL less than the mean for gestation. Usually features are not obvious unless the fetal haemoglobin is < 6 g/dL • Polyhydramions • Enlarged fetal heart • Ascites and pericardial effusions • Hyperdynamic fetal circulation (can be detected by Doppler ultrasound measuring increased velocities in the middle cerebral artery or aorta ) • Reducted fetalmovements • Abnormal CTG with reduced variability,eventually a ,,sinusoidal,, trace

41. Rhesus incompatibility: • The condition of the fetus is determined by the amount of maternal antibody transferred across the placena and the ability of the fetus to replace the red blood cells that have been destroyed.

42. Rhesus incompatibility: • In subsequent pregnancies , with Rh + fetus, the proces of antibody production and transfer may be accelerated, leading to the development of more significant anaemia. • In such cases, the fetal liver can manufacture additional red cells. However, this activity reduces the amount of protein manufactured by the fetal liver. In turn, the reduced protein production can lead to a decreased oncotic pressure within the fetal vascular system, resulting in fetal ascites and subcutaneous edema. At the same time , the severe fetal anaemia can lead to high output cardiac failure. This combination of findings is referred to as HYDROPS FETALIS.

43. Risk of Rh sensitization: Event Incidence% • Early pregnancy loss 3-5 • Elective abortion 6-20 • Ectopic pregnancy 5-8 • Amniocentesis 4-11 • Chorionic villous sampling 8-15 • Cordocentesis 30-50 • Antepartum trauma variable • Placental abruption low • Fetal demise variable • Manual placental extraction variable • External version variable

44. Immune hydrops • The abnormal collection of fluid in more than one area of the fetal body, such as ascites and pleural effusion, is termed hydrops. • Its causes usually are categorized as immune – such as isoimmunization- and nonimmune.

45. Immune hydrops • In immune hydrpos , excessive and prolonged hemolysis causes anaemia , which stimulates marked erythroid hyperplasia of the bone marrow as well as extramedullary hematopoesis in the spleen and liver with eventual hepatic dysfunction.

46. Immune hydrops • There may be cardiac enlargement and pulmonary hemorrhage. • Fluid collects in the fetal thorax, abdominal cavity, or skin. The placenta is markedly edematous, enlarged, and boggy, with large , prominent cotyledons and edematous villi.

47. Immune hydrops • Hydrothorax may be so severe as to restrict lung development, which causes pulmonary compromise after birth. • Ascites, hepatomegaly, and splenomegaly may lead to severe dystocia. • HYDROPIC CHANGES ARE EASILY SEEN BY SONOGRAPHY!!!!

48. Fetuses with hydrops may die in utero from profound anaemia and circulatory failure. • One sign of severe anaemia and impending death is the sinusoidal fetal heart rate pattern. • Hydropic changes in the placenta, leading to placentomegaly, can cause preeclampsia.

49. Hyperbilirubinemia: • Less severely affected infants may appear well at birth, only to become jaundiced within a few hours. • Marked hyperbilirubinemia, if untreated , can cause kernicterus, a from of central nervous system damage that specifically affects the basal ganglia and can lead to cerebral palsy.

50. Mortality: • Perinatal deaths from hemolytic disease caused by D-isoimmunization have decreased dramatically since adoption of the policy of routine administration of D- immunoglobulin to all D-negative women during or immediately after pregnancy. • Survival also has been increased by advances in antenatal and neonatal therapy : the seriously affected fetus can be identified and treated by antenatal transfusion or delivered preterm if necessary.