Transfusionsmedizin 2018; 8(02): 95-110
DOI: 10.1055/s-0043-121102
CME-Fortbildung
Georg Thieme Verlag KG Stuttgart · New York

Hämolytische Erkrankung des Fetus und Neugeborenen

Teil 1: Ätiologie, Pathogenese, Diagnostik und Therapie in der Schwangerschaft
Roland Axt-Fliedner
,
Sandra Wienzek-Lischka
,
Ulrich J. Sachs
,
Nina Cooper
,
Klaus-Peter Zimmer
,
Harald Ehrhardt
,
Gregor Bein
Further Information

Publication History

Publication Date:
06 June 2018 (online)

Die Schwangerschaftskomplikation „Hämolytische Erkrankung des Fetus und Neugeborenen“ kann unbehandelt zum Kindstod führen. Lesen Sie in Teil 1 des Beitrags über Ätiologie, Pathogenese, Diagnostik und Therapie in der Schwangerschaft. Der Teil 2 stellt die Diagnose und Therapie der hämolytischen Erkrankung des Neugeborenen sowie die Primärprophylaxe vor.

Kernaussagen
  • Während der Schwangerschaft kann die werdende Mutter Antikörper gegen Antigene auf fetalen Erythrozyten bilden.

  • Die fetale hämolytische Anämie wird durch maternale IgG-Antikörper bei fetomaternaler Blutgruppeninkompatibilität hervorgerufen.

  • Fortschritte in der Pränatalmedizin, der Neonatologie und Transfusionsmedizin führten in den letzten Jahren zu einem Paradigmenwechsel: Die frühzeitige Erkennung von Risikoschwangerschaften, Komplikationen und deren Management erfolgt heute weitgehend nicht invasiv.

  • Bei der Diagnostik der fetalen Anämie durch Doppler-Sonografie wird sich der Zusammenhang zwischen fetalem Hämatokrit und der Blutflussgeschwindigkeit in fetalen Gefäßen zunutze gemacht.

  • Hydrops fetalis ist eine Manifestation von Morbus haemolyticus fetalis.

  • Unbehandelt kann die seltene Schwangerschaftskomplikation „hämolytische Erkrankung des Fetus und Neugeborenen“ zum Kindstod führen.

  • Bei einer behandlungsbedürftigen fetalen Anämie ist die intrauterine Bluttransfusion die einzige therapeutische Option.

 
  • Literatur

  • 1 Levine P, Stetson RE. An unusual case of intra-group agglutination. JAMA 1939; 113: 126
  • 2 Landsteiner K, Wiener AS. An agglutinable factor in human blood recognized by immune sera for Rhesus blood. Exp Biol Med 1940; 43: 223
  • 3 Sebring ES, Polesky HF. Fetomaternal hemorrhage: Incidence, risk factors, time of occurrence, and clinical effects. Transfusion 1990; 30: 344-357
  • 4 Urbaniak SJ, Greiss MA. RhD haemolytic disease of the fetus and the newborn. Blood Rev 2000; 14: 44-61
  • 5 Woodrow JC, Donohoe WT. Rh-immunization by pregnancy: Results of a survey and their relevance to prophylactic therapy. Br Med J 1968; 4: 139-144
  • 6 Wilcox CR, Holder B, Jones CE. Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy. Front Immunol 2017; 8: 1294
  • 7 Palmeira P, Quinello C, Silveira-Lessa AL. et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012; 2012: 985646
  • 8 Vaughan JI, Manning M, Warwick RM. et al. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Med 1998; 338: 798-803
  • 9 Wagner T, Bernaschek G, Geissler K. Inhibition of megakaryopoiesis by Kell-related antibodies. N Engl J Med 2000; 343: 72
  • 10 Heathcote DJ, Carroll TE, Flower RL. Sixty years of antibodies to MNS system hybrid glycophorins: What have we learned?. Transfus Med Rev 2011; 25: 111-124
  • 11 Ishida A, Ohto H, Yasuda H. et al. Anti-M antibody induced prolonged anemia following hemolytic disease of the newborn due to erythropoietic suppression in 2 siblings. J Pediatr Hematol Oncol 2015; 37: e375-e377
  • 12 van Kamp IL, Klumper FJ, Bakkum RS. et al. The severity of immune fetal hydrops is predictive of fetal outcome after intrauterine treatment. Am J Obstet Gynecol 2001; 185: 668-673
  • 13 Pasman SA, Meerman RH, Vandenbussche FPHA. et al. Hypoalbuminemia: A cause of fetal hydrops?. Am J Obstet Gynecol 2006; 194: 972-975
  • 14 van den Akker ESA, de Haan TR, Lopriore E. et al. Severe fetal thrombocytopenia in Rhesus D alloimmunized pregnancies. Am J Obstet Gynecol 2008; 199: 387.e1-e4
  • 15 Ellis MI, Hey EN, Walker W. Neonatal death in babies with rhesus isoimmunization. Q J Med 1979; 48: 211-225
  • 16 Mollison PL. Mollisonʼs Blood Transfusion in clinical Medicine. 12th edition. Chichester, West Sussex: Wiley Blackwell; 2014
  • 17 Koelewijn JM, de Haas M, Vrijkotte TGM. et al. One single dose of 200 microg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy. Transfusion 2008; 48: 1721-1729
  • 18 de Haas M, Thurik FF, Koelewijn JM. et al. Haemolytic disease of the fetus and newborn. Vox Sang 2015; 109: 99-113
  • 19 Moise KJ, Argoti PS. Management and prevention of red cell alloimmunization in pregnancy: A systematic review. Obstet Gynecol 2012; 120: 1132-1139
  • 20 Chatziantoniou V, Heeney N, Maggs T. et al. A descriptive single-centre experience of the management and outcome of maternal alloantibodies in pregnancy. Transfus Med 2017; 27: 275-285
  • 21 Koelewijn JM, Vrijkotte TGM, van der Schoot CE. et al. Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: A population study in the Netherlands. Transfusion 2008; 48: 941-952
  • 22 Stetson B, Scrape S, Markham KB. Anti-M alloimmunization: management and outcome at a single institution. AJP Rep 2017; 7: e205-e210
  • 23 Nicolaides KH, Rodeck CH. Maternal serum anti-D antibody concentration and assessment of rhesus isoimmunisation. BMJ 1992; 304: 1155-1156
  • 24 Bowman JM. Treatment options for the fetus with alloimmune hemolytic disease. Transfus Med Rev 1990; 4: 191-207
  • 25 Judd WJ. Practice guidelines for prenatal and perinatal immunohematology, revisited. Transfusion 2001; 41: 1445-1452
  • 26 Moise KJ, Perkins JT, Sosler SD. et al. The predictive value of maternal serum testing for detection of fetal anemia in red blood cell alloimmunization. Am J Obstet Gynecol 1995; 172: 1003-1009
  • 27 Hackney DN, Knudtson EJ, Rossi KQ. et al. Management of pregnancies complicated by anti-c isoimmunization. Obstet Gynecol 2004; 103: 24-30
  • 28 Moise KJ. Fetal anemia due to non-Rhesus-D red-cell alloimmunization. Semin Fetal Neonatal Med 2008; 13: 207-214
  • 29 van Wamelen DJ, Klumper FJ. et al. Haas M de et al. Obstetric history and antibody titer in estimating severity of Kell alloimmunization in pregnancy. Obstet Gynecol 2007; 109: 1093-1098
  • 30 Bundesärztekammer. Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Richtlinie Hämotherapie) gemäß den §§ 12a und 18 des Transfusionsgesetzes.. Im Internet: http://www.bundesaerztekammer.de/aerzte/medizin-ethik/wissenschaftlicher-beirat/veroeffentlichungen/haemotherapie-transfusionsmedizin/richtlinie/ Stand: 03.02.2018
  • 31 Dekkers G, Treffers L, Plomp R. et al. Decoding the human immunoglobulin G-glycan repertoire reveals a spectrum of Fc-receptor- and complement-mediated-effector activities. Front Immunol 2017; 8: 877
  • 32 Sonneveld ME, Koelewijn J, de Haas M. et al. Antigen specificity determines anti-red blood cell IgG-Fc alloantibody glycosylation and thereby severity of haemolytic disease of the fetus and newborn. Br J Haematol 2017; 176: 651-660
  • 33 Lambin P, Debbia M, Puillandre P. et al. IgG1 and IgG3 anti-D in maternal serum and on the RBCs of infants suffering from HDN: Relationship with the severity of the disease. Transfusion 2002; 42: 1537-1546
  • 34 Finn R, Clarke CA, Donohoe WTA. et al. Experimental studies on the prevention of Rh haemolytic disease. BMJ 1961; 1: 1486-1490
  • 35 Dooren MC, Kuijpers RW, Joekes EC. et al. Protection against immune haemolytic disease of newborn infants by maternal monocyte-reactive IgG alloantibodies (anti-HLA-DR). Lancet 1992; 339: 1067-1070
  • 36 Neppert J, v. Witzleben-Schürholz E, Zupanska B. et al. High incidence of maternal HLA A, B and C antibodies associated with a mild course of haemolytic disease of the newborn. Group for the Study of Protective Maternal HLA Antibodies in the Clinical Course of HDN. Eur J Haematol 1999; 63: 120-125
  • 37 Gemeinsamer Bundesausschuss. Richtlinien des Gemeinsamen Bundesausschusses über die ärztliche Betreuung während der Schwangerschaft und nach der Entbindung („Mutterschafts-Richtlinien“) in der Fassung vom 10. Dezember 1985 (veröffentlicht im Bundesanzeiger Nr. 60a vom 27. März 1986). Letzte Änderung: 21.04.2016 BAnz AT 19.07.2016 B5.. Im Internet: https://www.g-ba.de/informationen/richtlinien/19/ Stand: 17.01.2018
  • 38 Avent ND. Prenatal testing for hemolytic disease of the newborn and fetal neonatal alloimmune thrombocytopenia – current status. Expert Rev Hematol 2014; 7: 741-745
  • 39 Kähler C, Gembruch U, Heling KS. et al. Empfehlungen der DEGUM zur Durchführung von Amniozentese und Chorionzottenbiopsie. Ultraschall Med 2013; 34: 435-440
  • 40 Scheffer PG, van der Schoot CE, Page-Christiaens G. et al. Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7-year clinical experience. BJOG 2011; 118: 1340-1348
  • 41 Wienzek-Lischka S, Krautwurst A, Fröhner V. et al. Noninvasive fetal genotyping of human platelet antigen-1a using targeted massively parallel sequencing. Transfusion 2015; 55: 1538-1544
  • 42 Giles WB, Trudinger BJ. Umbilical cord whole blood viscosity and the umbilical artery flow velocity time waveforms: a correlation. Br J Obstet Gynaecol 1986; 93: 466-470
  • 43 Huikeshoven FJ, Hope ID, Power GG. et al. A comparison of sheep and human fetal oxygen delivery systems with use of a mathematical model. Am J Obstet Gynecol 1985; 151: 449-455
  • 44 Kirkinen P, Jouppila P, Eik-Nes S. Umbilical vein blood flow in rhesus-isoimmunization. Br J Obstet Gynaecol 1983; 90: 640-643
  • 45 Oepkes D, Seaward PG, Vandenbussche FPHA. et al. Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 2006; 355: 156-164
  • 46 Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2008; 112: 164-176
  • 47 Bellini C, Hennekam RCM, Fulcheri E. et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet A 2009; 149 A: 844-851
  • 48 Picklesimer AH, Oepkes D, Moise KJ. et al. Determinants of the middle cerebral artery peak systolic velocity in the human fetus. Am J Obstet Gynecol 2007; 197: 526.e1-4
  • 49 Staudach A. Fetale Anatomie im Ultraschall. Berlin, Heidelberg, New York: Springer; 1986
  • 50 Mari G, Deter RL, Carpenter RL. et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000; 342: 9-14
  • 51 Mari G, Zimmermann R, Moise KJ. et al. Correlation between middle cerebral artery peak systolic velocity and fetal hemoglobin after 2 previous intrauterine transfusions. Am J Obstet Gynecol 2005; 193: 1117-1120
  • 52 Mari G, Detti L, Oz U. et al. Accurate prediction of fetal hemoglobin by Doppler ultrasonography. Obstet Gynecol 2002; 99: 589-593
  • 53 van Dongen H, Klumper FJCM, Sikkel E. et al. Non-invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies. Ultrasound Obstet Gynecol 2005; 25: 341-345
  • 54 Leung TY, Lao TT. Thalassaemia in pregnancy. Best Pract Res Clin Obstet Gynaecol 2012; 26: 37-51
  • 55 Gembruch U, Holzgreve W. The Fetus with non-immune Hydrops. In: Harrison MR. ed. The unborn Patient. The Art of Science of fetal Therapy. 3rd edition. Philadelphia: W.B. Saunders; 2001: 525-582
  • 56 Merz WM, Kübler K, Fimmers R. et al. Circulating N-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment. Pediatr Res 2012; 72: 174-178
  • 57 Nicolaides KH, Soothill PW, Clewell WH. et al. Fetal haemoglobin measurement in the assessment of red cell isoimmunisation. Lancet 1988; 1: 1073-1075
  • 58 Dodd JM, Windrim RC, van Kamp IL. Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes. Cochrane Database Syst Rev 2012; (09) CD007096
  • 59 Zwiers C, van Kamp I, Oepkes D. et al. Intrauterine transfusion and non-invasive treatment options for hemolytic disease of the fetus and newborn – review on current management and outcome. Expert Rev Hematol 2017; 10: 337-344
  • 60 Harman CR, Bowman JM, Manning FA. et al. Intrauterine transfusion – intraperitoneal versus intravascular approach: a case-control comparison. Am J Obstet Gynecol 1990; 162: 1053-1059
  • 61 Lewis M, Bowman JM, Pollock J. et al. Absorption of red cells from the peritoneal cavity of an hydropic twin. Transfusion 1973; 13: 37-40
  • 62 Taylor WW, Scott DE, Pritchard JA. Fate of compatible adult erythrocytes in the fetal peritoneal cavity. Obstet Gynecol 1966; 28: 175-181
  • 63 Westgren M, Selbing A, Stangenberg M. Fetal intracardiac transfusions in patients with severe rhesus isoimmunisation. Br Med J (Clin Res Ed) 1988; 296: 885-886
  • 64 Scheier M, Hernandez-Andrade E, Fonseca EB. et al. Prediction of severe fetal anemia in red blood cell alloimmunization after previous intrauterine transfusions. Am J Obstet Gynecol 2006; 195: 1550-1556
  • 65 Rodeck CH, Nicolaides KH, Warsof SL. et al. The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions. Am J Obstet Gynecol 1984; 150: 769-774
  • 66 Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynecol 1985; 153: 655-660
  • 67 Mandelbrot L, Daffos F, Forestier F. et al. Assessment of fetal blood volume for computer-assisted management of in utero transfusion. Fetal Ther 1988; 3: 60-66
  • 68 Viëtor HE, Kanhai HH, Brand A. Induction of additional red cell alloantibodies after intrauterine transfusions. Transfusion 1994; 34: 970-974
  • 69 Schonewille H, Klumper FJCM, van de Watering LMG. et al. High additional maternal red cell alloimmunization after Rhesus- and K-matched intrauterine intravascular transfusions for hemolytic disease of the fetus. Am J Obstet Gynecol 2007; 196: 143.e1-6
  • 70 Trevett TN, Dorman K, Lamvu G. et al. Antenatal maternal administration of phenobarbital for the prevention of exchange transfusion in neonates with hemolytic disease of the fetus and newborn. Am J Obstet Gynecol 2005; 192: 478-482
  • 71 Yinon Y, Visser J, Kelly EN. et al. Early intrauterine transfusion in severe red blood cell alloimmunization. Ultrasound Obstet Gynecol 2010; 36: 601-606
  • 72 Canlorbe G, Macé G, Cortey A. et al. Management of very early fetal anemia resulting from red-cell alloimmunization before 20 weeks of gestation. Obstet Gynecol 2011; 118: 1323-1329
  • 73 Poissonnier MH, Picone O, Brossard Y. et al. Intravenous fetal exchange transfusion before 22 weeks of gestation in early and severe red-cell fetomaternal alloimmunization. Fetal Diagn Ther 2003; 18: 467-471
  • 74 Lindenburg ITM, van Kamp IL, van Zwet EW. et al. Increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation. BJOG 2013; 120: 847-852
  • 75 Zwiers C, Lindenburg ITM, Klumper FJ. et al. Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. Ultrasound Obstet Gynecol 2017; 50: 180-186
  • 76 Pasman SA, Claes L, Lewi L. et al. Intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in Leuven. Facts Views Vis Obgyn 2015; 7: 129-136
  • 77 Lindenburg IT, Smits-Wintjens VE, van Klink JM. et al. Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: The LOTUS study. Am J Obstet Gynecol 2012; 206: 141.e1-8
  • 78 Wong KS, Connan K, Rowlands S. et al. Antenatal immunoglobulin for fetal red blood cell alloimmunization. Cochrane Database Syst Rev 2013; (05) CD008267
  • 79 Ruma MS, Moise KJ, Kim E. et al. Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization. Am J Obstet Gynecol 2007; 196: 138.e1-6