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New alternatives for management of isoimmunization

New alternatives for management of isoimmunization Nuevas alternativas en el manejo de la isoinmunización. Leonardo Pereira MD Assistant Professor Maternal-Fetal Medicine Oregon Health & Science University. Causes of fetal anemia. Red cell alloimmunization

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New alternatives for management of isoimmunization

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  1. New alternatives for management of isoimmunization Nuevas alternativas en el manejo de la isoinmunización Leonardo Pereira MD Assistant Professor Maternal-Fetal Medicine Oregon Health & Science University

  2. Causes of fetal anemia Red cell alloimmunization hemolytic disease of the newborn (EF) direct bone marrow suppression Viral infections parvovirus B19 toxoplasmosis coxsackie cytomegalovirus Hemoglobinopathies alpha-thalassemia Genetic Disorders Fanconi syndrome TAR syndrome Aase syndrome Twin to Twin Transfusion

  3. Timeline: hemolytic disease of the newborn HDN described Amniotic fluid bilirubin measurement Fetal RhD Maternal Plasma Maternal serum antibody titers Discovery of Rh factor Landsteiner & Weiner Liley Curve ΔOD450 MCA Doppler Noninvasive detection Queenan Modification ΔOD450 Postnatal Exchange Transfusions Prevention α-RhD Ig 1990 1960 1970 2000 1950 1980 1940

  4. Fetal antigenic determination Amniocentesis, CVS, cordocentesis samples can be used to determine fetal antigen status by DNA typing 100% accuracy in 390 samples Bennett et al. 1993 Molecular analysis of maternal plasma: fetal DNA for RhD 100% accuracy in 45 fetuses second/third trimester Lo et al. N Engl J Med 1998;339:1734-8. PCR from cell free DNA in maternal serum 100% accuracy in 137 fetuses (including 21 female fetuses) Finning et al. Transfusion 2002;42:1079-85. Possible utility in embryo selection for sensitized mothers

  5. Mari et al. N Eng J Med 2000

  6. MCA-PSV

  7. Fetal Hemoglobin (g/dl) by Gestational Age Weeks Gestation 18 12.3 10.6 8.9 6.95.8 20 12.9 11.1 9.3 7.26.1 22 13.4 11.6 9.7 7.56.4 24 13.9 12.0 10.1 7.86.6 26 14.3 12.3 10.3 8.06.8 28 14.6 12.6 10.6 8.26.9 30 14.8 12.8 10.8 8.37.1 32 15.2 13.1 10.9 8.57.2 34 15.4 13.3 11.2 8.67.3 36 15.6 13.5 11.3 8.77.4 38 15.8 13.6 11.4 8.97.5 40 16.0 13.8 11.6 9.07.6 mild moderate severe anemia anemia anemia Multiples of the Median 1.16 1.00 0.84 0.650.55 Hgb Values Mari, et al. N Eng J Med 2000.

  8. Current evidence supporting MCA-PSV Doppler velocimetry Initial prospective study of 16 fetuses: 14 anti-D, 2 anti-c Mari et al. Ultrasound Obstet Gynecol 1995;5:400-5. Since then several prospective and retrospective studies: over 200 additional cases Rbc alloimmunization and parvovirus B19 Scott et al. Prenat Diagn 1998;18:1143-8. Teixeira et al. Ultrasound Obstet Gynecol 2000;15:205-8. Delle Chiaie et al. Ultrasound Obstet Gynecol 2001;18:232-6. Mari et al. N Eng J Med 2000;342:9-14. Zimmermann et al. Br J Obstet Gynecol 2002;109:746-52. Mari et al. Ultrasound Obstet Gynecol 2002;99:589-93.

  9. Current evidence supporting MCA-PSV Doppler velocimetry Sensitivity 87-90% Specificity 88-100% PPV 53-74% NPV 98-100% Data combined from 7 studies: rbc alloimmunization and parvovirus B19

  10. Prediction of fetal anemia by MCA-PSV Doppler compared to Amniocentesis 4 Comparative Studies N = 28Nishie EN, et al. Am J Obstet Gynecol 2003;188:214-9. N = 28Pereira L et al. Am J Obstet Gynecol 2003;189:1002-6. N = 38Bullock R, et al. Ultrasound Obstet Gynecol 2005;25:331-4. N = 165Oepkes D, et al. N Engl J Med 2006;355:156-64.

  11. Prediction of fetal anemia by MCA-PSV Doppler compared to Amniocentesis Conventional Management of Fetal Alloimmunization Compared to Management by Middle Cerebral Artery Peak Systolic Velocity. Purpose: To determine the predictive accuracy of MCA-PSV measurements for moderate or severe fetal anemia in erythrocyte alloimmunized pregnancies To compare management of alloimmunized pregnancies by serial MCA-PSV measurements to our conventional management Pereira L et al. Am J Obstet Gynecol 2003;189:1002-6.

  12. Antibody Specificity n = 28 D 9 Kell 1 Kell and Kidd 1 D and C 3 D and M 2 D, C, E, Kidd 1 D, C, e, Kidd 1 E 3 c 2 C and Kidd 1 u 1 anticoltan 1 Kidd 1 Duffy 1 Distribution of Erythrocyte Antibody Specificities

  13. Conventional Management • Maternal serum titers every 3-4 weeks • Indications for amniocentesis and US • • critical threshold • • earlier if prior affected pregnancy • Amniocentesis every 2-4 weeks, US every 2 weeks • Indications for PUBS • • abnormal amniocentesis • • US evidence of fetal hydrops • • Kell sensitization • Transfusion for moderate or severe anemia • PUBS repeated as necessary, weekly US

  14. Results Fetuses Total Procedures 24/28 (86%) 49 Amniocenteses 9/28 (32%) 14 PUBS

  15. Diagnosis of Anemia 28 Cases Diagnosis 20 non-anemic 2 PUBS, 18 neonatal Hct 3 mild 3 PUBS 1 moderate 1 PUBS 4 severe 3 PUBS, 1 neonatal Hct

  16. Conventional MCA-PSV PUBS NO PUBS PUBS NO PUBS 1 Anti-D,C, e,Kidd 4 Anti-D 1 Anti-D,C, e,Kidd 4 Anti-D MODERATE OR SEVERE ANEMIA 1 Anti-D 1 Anti-u 2 Anti-Kell 1 Anti-C 1 Anti-c 1 Anti-D,C, E,Kidd MILD ANEMIA OR NORMAL HEMOGLOBIN 9 19 7 21

  17. Predictive Accuracy Amniocentesis MCA-PSV Sensitivity 80 (4/5) 100(5/5) Specificity 78 (18/23) 91(21/23) PPV 44 (4/9) 71(5/7) NPV 95 (18/19) 100(21/21) FP rate 56 (5/9) 28(2/7) FN rate 5 (1/19) 0(0/21) RR (95%CI) 3.7 (1.5-9.0) 11.5(3.1-43.2)

  18. Predictive Accuracy Initial Study (28) Current Totals(42) Sensitivity 100 90 Specificity 91 91 PPV 71 75 NPV 100 97 FP rate 28 25 FN rate 0 14 RR (95%CI) 11.5 22.5

  19. Current evidence MCA-PSV Doppler Amniocentesis Sensitivity 53-86 64-100 Specificity 71-78 81-91 PPV 44-100 47-75 NPV 95-96 97-100 N =259 Cummulative ranges from 4 trials

  20. Potential Benefits of Management by MCA-PSV • 14,000 cases of alloimmunization per year in the U.S. • Avoid 24,500 amniocenteses and 900 PUBS • Avoid 1 pregnancy loss/preterm delivery for every • 100 patients; 142 nationwide per year • Avoid worsening sensitization from procedure • related bleeding complications – TPH risk 2-10% following amniocentesis, 50% following PUBS

  21. Limitations of MCA-PSV Angle of insonation - underestimate the MCA-PSV Distal MCA - underestimate the MCA-PSV Blood viscosity - decreased sensitivity after multiple transfusions (> 3) Fetal cerebral hemodynamics - anatomic lesions (severe ventriculomegaly, calcified cystic lesions, solid tumors, or vascular malformations) - accuracy of MCA-PSV not well characterized

  22. Limitations of MCA-PSV Dependent on normal left ventricular cardiac output - fetal hydrops, CHD, cardiomyopathy Decreased specificity of MCA-PSV after 35 weeks gestation Multiple factors affect the MCA-PSV: fetal behavioral state, maternal medications, labor Intermittent vascular constriction - overestimate the MCA-PSV (may explain several reported cases where an elevated MCA-PSV measurement has not been reproducible)

  23. Areas for Future Research Accuracy of MCA-PSV in fetuses with anemia from other etiologies MCA-PSV in clinical practice Fetuses with compromised left-sided cardiac output Fetuses with platelet or neutrophil disorders

  24. Conclusion MCA-PSV accurately predicted moderate to severe fetal anemia Compared to conventional management, MCA-PSV may have a better predictive accuracy for moderate or severe anemia in alloimmunization Management by MCA-PSV may eliminate the need for amniocentesis and reduce the number of PUBS performed in alloimmunized pregnancies

  25. Management protocol Identify at risk pregnancies: prior affected pregnancy, critical maternal serum titer, Kell sensitized, other suspected etiology Weekly measurements of the MCA-PSV (18-20 weeks - 35 weeks) If MCA < 1.5 MoM and steady in zone then measure every 10-14 days If MCA < 1.5 MoM and increasing in zones then follow every 2-7 days If MCA > 1.5 MoM then cordocentesis with possible transfusion or repeat in 12-18 hours If sonographic evidence of hydrops then cordocentesis with possible transfusion Revert back to “conventional management” if: > 3 intrauterine transfusions, or one of the cases mentioned previously where reliability of MCA-PSV not yet established

  26. Thank you

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