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RH-ISOIMMUNISED PREGNANCY prevention and management

RH-ISOIMMUNISED PREGNANCY prevention and management. Alloimmune anaemias. Fetal and neonatal anaemias because of hemolysis caused by circulating destructive antibodies in the perinate Antibodies produced in the maternal immune system in response to fetal red cell antigen exposure. PATHOGENESIS.

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RH-ISOIMMUNISED PREGNANCY prevention and management

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  1. RH-ISOIMMUNISED PREGNANCYprevention and management

  2. Alloimmune anaemias Fetal and neonatal anaemias because of hemolysis caused by circulating destructive antibodies in the perinate Antibodies produced in the maternal immune system in response to fetal red cell antigen exposure

  3. PATHOGENESIS Fc receptor mediated transport Mononuclear phagocyte IgG Fc receptor PLACENTA D+ RBC D+ RBC HAEMOLYSIS

  4. The Rh Blood Group • Incidence: • India: 4 - 6 % • Chinese: 1% • Blacks: 7- 8 % • Europeans: 15 % • Basques: 30 % • Isoimmunised pregnancy : U.S. 6.8 / 1000 live births

  5. GENETICS – the rh antigen 1p34 Rhesus locus on chromosome 1 D gene CE gene HOMOZYOUS RH D POSITIVE All offspring Rh positive CE gene HETEROZYGOUS RH D POSITIVE 50 % fetuses Rh negative CE gene RH D NEGATIVE

  6. OTHER BLOOD GROUPS CAUSING HYDROPS

  7. Pathophysiology • Blood cells : 21 days of gestation • Rh antigen : 38 days / 7 weeks • Fetal cells in maternal blood : 10 weeks • Immunity in mother: • Primary response Ig M • Secondary response Ig G • FcγR mediated phagocytosis 17-18 weeks

  8. Immune complex RBC membrane damage Extravascular hemolysis Anaemia Compensatory responses inadequate Insufficient time adequate Extramedullary hematopoesis Severe anaemia Increased hematopoesis death hepatosplenomegaly Minimal or no fetal effects Portal hypertension Liver dysfunction high output cardiac failure Neonatal hyperbilirubinaemia hydrops

  9. Fetal testing for RhD gene • CVS • CORDOCENTESIS • AMNIOCENTESIS (genotype) • PCR • Sensitivity – 89.7% • Specificity – 100% accuracy 99.7% • Flow cytometry : fetal cells from maternal blood • Free fetal DNA from maternal serum

  10. PATHOGENESIS • 17 % of Rh –ve women are immunised by a single Rh +ve pregnancy (without prophylaxis) • Risk of alloimmunisation increases with advancing gestation

  11. MECHANISM OF ALLOIMMUNISATION

  12. FACTORS ENHANCING FETOMATERNAL HAEMORRHAGE 1 in 1000 deliveries have excessive FMH; risk factors identify only 50%

  13. INCIDENCE OF IMMUNISATION IS MUCH LESSER • 30% non-responders • Associated ABO incompatibility • Du positive • Small size of inoculum (<0.1 ml) • Low potency/poor efficacy of anti-D

  14. TESTS FOR TPH • Kleihauer Braun Betke test: • Fetal RBCs resistant to acid elution (citric acid phosphate buffer pH 3.5) • Maternal RBCs appear like ghost cells • % of fetal RBCs against maternal cells • Vol of TPH=% fetal RBCs x 50 • Fetal blood volume = MBV x mat Hct x % fetal cell newborn Hct • Can detect 0.2 ml in 5 l of maternal circulation • Additional Anti-D 150µg for every 6 ml RBCs

  15. Tests…. • Erythrocyte rosette test : qualitative • Enzyme linked antiglobulin test : • Quantitative • Detects Rh +ve cells maternal / fetal • Flow cytometry : • Uses fluorescent conjugated monoclonal Anti-D

  16. OUTCOME 50 % 25 – 30 % 20 – 25 % Mild or no anaemia at birth Hb > 12g% Moderate Anaemia Hb > 9 g% Require treatment in neonatal period Hydrops IUD or Neonatal death

  17. PREVENTION • Anti-D should be given to all Rh –ve unsensitised mothers : • Ectopic pregnancy • All induced abortions • Spontaneous complete or incomplete abortions > 12 weeks • Threatened abortion after 12 weeks; before 12 weeks only if bleeding heavy, persistent or painful • Potentially sensitizing events during pregnancy: • Invasive prenatal procedures • antepartum hemorrhage • External cephalic version • Abdominal trauma • Intrauterine death • Antenatal and postnatal prophylaxis

  18. RECOMMENDATIONS • Antenatal : • RCOG : 2 Doses at 28 and 34 weeks (min 500 iu) • ACOG : single dose at 28 weeks • Postnatal : • If baby blood group Rh +ve to administer within 72 hrs (upto 9-10 days) • Identify causes of large FMH; estimate volume of FMH; adequate dose to be given • Large FMH likely in: • Traumatic deliveries ; LSCS • Manual removal of placenta • Stillbirths; IUD • Trauma • Multiple pregnancy • Unexplained hydrops

  19. DOSE : • 500 iu = 100 µg • 300 µg sufficient for 30 ml of FMH • Given IM in the deltoid • 250 iu (50µg) < 20 weeks • 500 iu > 20 weeks • Postnatal dose : • 1000-1500 iu (300µg) • If volume of FMH high, adequate dose calculated and max 5 vials given at a time • If bleeding continues during pregnancy after 20 weeks, Anti D repeated 6 weekly

  20. NON-SENSITIZED RH-NEGATIVE MOTHER • Confirm husband Rh +ve • Monthly ICTs starting 18-20 w • Antenatal Anti-D (300µg) given at 28 weeks if ICT –ve • After delivery baby blood group and DCT done; if Rh +ve Anti-D 300 µg given within 72 hrs • If risk factors for large FMH present, Kleihauer Betke test done and dose administered accordingly • Delivery : avoid methergin, early cord clamping, avoid manual removal of placenta

  21. EVALUATION OF Rh SENSITIZED PATIENT • Previous obstetric history: • Severity of disease increases progressively with each successive pregnancy • Onset of disease earlier • The first intervention 10 weeks before earliest previous death, hydrops, IUT or birth of an affected baby

  22. EVALUATION OF Rh SENSITIZED PATIENT : ANTIBODY LEVELS • Agglutination tests : saline & colloid not done • Indirect Coomb’s test : • Maternal antiglobulin titre • Reported as integer of greatest tube dilution with +ve agglutination reaction (1: 8 / 1:16) • CRITICAL TITRE is that associated with significant risk for hydrops (1:16) • Titre above the critical value indication for invasive testing • Useful only in the first sensitized pregnancy, previous mild disease • Do not correlate with severity of fetal disease • Sudden rise in titre more significant than absolute value in severe disease • Amount of circulating Anti-D : • > 15 iu/ml threshold for an invasive test

  23. EVALUATION OF Rh SENSITIZED PATIENT : in vitro assays • MONOCYTE MONOLAYER ASSAY • ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY ASSAY • MONOCYTE CHEMILUMINESCENCE TEST • measure the ability of anti-D antibodies to mediate red cell destruction thru hemolysis • Superior to ICT in predicting severity of disease and need for exchange transfusion

  24. ULTRASOUND Hepatic length Splenic length Umbilical vein diameter Abdominal circumference Placental thickness Polyhydramnios Cardiomegaly (Divakaran TG et al, Obstet Gynecol 2001) Hydrops : end stage disease; Hb 1/3 of normal Only 2/3 of anaemic fetuses have hydrops Doppler assessment : Middle cerebral artery doppler Not proven reliable

  25. Pleural effusion placentomegaly SCALP EDEMA

  26. Single morphology USG • Dilated umbilical vein > 2SD for gest age • Placental thickness > 4 cm for any gestation • Double bowel sign both sides of bowel seen • Pericardial effusion 2 mm rim • Liver enlargement > 90 % for gest age • Splenic enlargement > 90-95%; >2 SD for gest age • Splenic perimeter (longitudinal + transverse)x1.57

  27. Multiple morphologic USG • Progression of hydrops • Polyhydramnios • Placentomegaly • Hepatomegaly • Pericardial effusion • Ascites • Scalp edema • Pleural effusion • Role of ultrasound • Identifying and quantitating the severity of fetal disease • Lesser value in excluding presence of disease • Lesser value in predicting the course of disease

  28. DOPPLER IN Rh ISOIMMUNISATION • Non invasive technique to detect fetal anemia due to Rh alloimmunisation • > 70 % invasive testing could be avoided • Mari et al ;NEJM 2000 • Blood velocity ↑ during anemia due to: • ↑cardiac output • ↓ in bl viscosity • Fetal MCA is the optimal vessel for measurement of peak systolic velocity for detection of fetal anemia: • Cerebral art respond quickly to hypoxia • Easily visualized with an angle of insonation close to 0° • Low intra and interobserver variability

  29. DOPPLER MIDDLE CEREBRAL ARTERY Technique • Transverse view of the fetal brain at the level of the biparietal diameter, which includes thalami & cavum septi pellucidi is obtained • Circle of willis is imaged with color Doppler • MCA seen as a major lateral branch of circle of Willis, running anterolaterally at borderline between anterior & middle cerebral fossae

  30. Technique cont… • Proximal 2 mm of MCA after its origin from ICA is examined (systolic velocity decreases with distance from point of origin of this vessel) • Angle between USG beam and bl flow is kept as close to 0 deg as possible • Apply minimal pressure to maternal abdomen with transducer, as fetal head compression is associated with alterations of intracranial arterial waveforms • Should be recorded during fetal inactivity • Waveforms (b/w 5-6) should be similar to each other • Highest PSV is measured

  31. The blood velocity increases with advancing gestation, and this is associated with decrease in PI

  32. Middle Cerebral Artery Flow velocity waveform in the fetal middle cerebral artery in a severely anemic fetus at 22 weeks (left) and in a normal fetus (right). In fetal anemia, blood velocity is increased

  33. DOPPLER IN Rh ISOIMMUNISATION • Prospective, multicentric trial (n=111, 7 centers) • The optimal threshold values for MCA PSV • 1.29 MOM for mild anemia • 1.5 MOM for moderate anemia • 1.55 MOM for severe anemia • Classification of anemia • Mild – Hb conc 0.84-0.65 MOM • Moderate - <0.65-0.55 MOM • Severe - <0.55 MO • Senst – 100% • False positive – 12% • PPV – 65% • NPV – 100% Mari et al; NEJM.2000

  34. DOPPLER IN Rh ISOIMMUNISATION Monitoring at-risk patients • Perform Doppler weekly for 3 consecutive times • If MCA PSV is <1.5MOM, calculate the slope of increase between the 3 measurements • Slope <1.95 – Rpt at 10-14 days interval • Slope at least 1.95 - Rpt at 7 days interval • If MCA PSV is at least 1.5MOM + USG findings consistent with anemia – FBS • If MCA PSV is at least 1.5MOM + no USG findings of anemia- Rpt MCA later that day or within 24 hrs to confirm elevation – FBS Detti et al 2002, AJOG

  35. DOPPLER IN Rh ISOIMMUNISATIONAccuracy of MCA doppler studies

  36. DOPPLER IN Rh ISOIMMUNISATION MCA PSV is less useful after 35 weeks (↑ false positive) • No convincing explanation • Velocity ∞ pressure gradient & square of radius • After 35 wks pressure gradient shows variation leading to ↑ overlap b/w affected & inaffected fetus • ↑ diff in compliance of vessel leading to diff radius

  37. MCA PSV in predicting anemia after IUT After one IUT • MCA PSV -1.69MOM –pred of sev anemia • Sensitivity 100% • Specificity 94% • MCA PSV -1.32mom- pred of mod anemia • Sensitivity 100% • Specificity 63% Detti et al,Am J Obstet Gynecol,2001 After two IUT • MCA PSV is assessed on the day third transfusion is scheduled (based on traditional criteria). If < 1.50 MOM, reassess every 3 days. If > 1.50 MOM, IUT is done Mari et al AJOG 2005

  38. Doppler in other arteries • Results of other vessels are disappointing as majority are found perpendicular to insonating Doppler beam, so PSV is underestimated Usg finding sensitivity specificity false + Mean velocity (aorta) 53 91 <9 Peak aortic velocity 64 73 26 MCA PSV 100 85-88 12-15 Splenic artery 87.5 91-95 5-8.8 Splenic art PSV 100 20.8 Moise et al, Obstet gynecol survey 2000 • Venous & intracardiac studies from AV valves, ductus venosus, hepatic vein, IVC are not good predictors Hecher el al Obstet Gynecol 1995

  39. DOPPLER IN Rh ISOIMMUNISATION Comparing Doppler & USG parameters Prospective study, n=16 Dukler et al, AJOG 2003

  40. MCA PSV Vs Amniocentesis • Prospective, international, multicenter study • 165 women with alloimmunized pregnancies MCA PSV can safely replace invasive testing in the management of Rh-alloimmunized pregnancies Oepkes D et al, NEJM2006 Jul 13;355(2):156-64

  41. NON-INVASIVE TECHNIQUES • Fetal movement count • Absent breathing movements • Abnormalities in NST, sinusoidal pattern, late decelerations: late signs • Fetal ECG changes

  42. INDICATIONS FOR INVASIVE TESTING • HISTORY • Hydropic still birth • Fetal transfusions • Neonatal exchange transfusions • Maternal serology • Critical titre • Sudden rise in titre • Fetal examination • Suspicious features : rising AC, placental edema, ascites, hydrops

  43. AMNIOCENTESIS • Amniotic fluid bilirubin α hemolysis • Spectrophotometric quantification of bilirubin by assessment of OD 450 value • Beware contamination by blood, meconium, exposure to light, passage of needle thru placenta

  44. LILEY CURVES From 27-35 weeks Zone 3 and 80% zone 2 Severely affected Indication for cordocentesis and IUT Mild-moderate affectation; Repeat in 1-2 weeks Unaffected or mildly affected; Repeat after 4 weeks

  45. Bowman curve The Queenan graph 14-40 weeks Robertson’s zones

  46. CORDOCENTESIS • 1973 : by hysterotomy • 1978 : fetoscopy • 1983 : Daffos et al ultrasound guidance • Cord blood obtained under ultrasound guidance from placental attachment or intrahepatic portion of the hepatic vein • Blood sent for • Blood group • DCT • Reticulocyte count • Fetal loss rate 1.9% • Complications : exsanguination, intra-amniotic bleeding, bradycardia, cord tamponade, worsens alloimmunisation

  47. Indications for fetal transfusion • OD 450 in zone III or rising OD450 to 80% zone II • USG evidence of hydrops • Fetal anaemia on cordocentesis hct < 30%

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