Fetal transfusion and neonatal exchange transfusion – trends, indications and methods A/Prof Helen Liley Newborn Medicine – Mater Mothers’ Hospital Mater Research – The University of Queensland Australia

Haemolytic disease of the fetus and newborn can have diverse outcomes, including lifethreatening hydrops and brain damage due to kernicterus. In many parts of the world, the severe adverse outcomes have gone from being common to being a rare occurrence. Nevertheless, the global burden of disease from haemolytic disease and other causes of fetal anaemia remains high.

Levine: Rh antigen cause of HDN Darrow: fetal red cells stimulate Ab in mother, then Ab X placenta and destroys baby’s cells: propose Ab to fetal Hb DIAGNOSIS AND TREATMENT Early delivery, exchange transfusion 1961: Liley chart: disease assessment 1963: Liley intrauterine transfusion PREVENTION Antenatal immunoprophylaxis DIAGNOSIS Rh proteins and genes sequenced Louyse Bourgeois describes twins with hydrops and kernicterus 1609 1932 1938 1940 1941 1943 1960s 1970s 1980s 1990s Diamond et al: Hydrops and kernicterus were different aspects of same disease: erythroblastosis fetalis . Cause then unknown. PREVENTION Rh Ig experiments Gorman, Freda, Pollock (USA) Clarke, Finn (UK) TREATMENT Intravascular intrauterine transfusion Landsteiner and Weiner discover “Rhesus factor” Fisher and Race: describe CDE system for Rh ASSESSMENT MCA Doppler There have been many landmarks in the understanding of the pathophysiology, diagnosis, treatment and prevention of haemolytic disease of the fetus and newborn, and it now stands as one of the finest examples of how a common lifethreatening and disabling disease can be prevented and managed. Rh haemolytic disease was the first and pioneering example of intrauternine diagnosis and treatment. Immunoprophylaxis using RhD immunoglobulin was one of the first and most successful forms of immunotherapy. The use of non-invasive techniques to diagnose fetal anaemia and to perform fetal blood typing have also been critical breakthroughs in improving outcomes.

Mater Mothers’ Hospital, Brisbane, Australia

Mater Mothers’ Hospital >10,000 births per year Referral centre for fetal management of haemolytic disease 79 bed Neonatal Intensive and Special Care Service

2003-2016 162 fetal transfusions for 80 fetuses 124 intrauterine transfusions for Rh or other haemolytic disease of the fetus and newborn 38 for other reasons 48 exchange transfusions in 48 babies 40 for RhD, other Rh or Kell HDFN 2 ABO 6 other (e.g. pyruvate kinase deficiency, hereditary spherocytosis, twin-twin transfusion syndrome)

Intrauterine transfusion for haemolytic disease The maternal fetal medicine specialists at our hospital perform an average of about 12 intrauterine transfusions per year, and while the number fluctuates from year to year, there is no particular trend towards an increase or decrease over the last 14 years. This graph shows the number of transfusions per year and number of fetuses transfused per year for 2003-2016, in this case for infants with haemolytic disease.

Intrauterine transfusion – for causes other than haemolytic disease There is also a steady incidence of intrauterine transfusions for other causes of fetal anaemia, mostly parvovirus. All but 6 were for fetal anaemia due to parvovirus

Exchange transfusions Interestingly, while exchange transfusion has been fairly uncommon over the last 14 years, the incidence remained fairly steady until 2013, then we haven’t done an exchange transfusion since.

Potential causes of decrease in exchange transfusions effective RhD immunoprophylaxis Patient blood management Extended cross-matching for girls and women of childbearing potential trends to smaller family size improved screening effective intrauterine treatment early use of intensive phototherapy for severe neonatal jaundice. We don’t know the exact reasons, but these I think are among the most likely. The incidence of haemolytic disease is gradually declining in Australia, for a variety of reasons

NHMRC, 1999 RECOMMENDATIONS 625 IU: delivery, sensitising events + assess fetomaternal haemorrhage 250 IU: sensitising events < 12wk events Antenatal prophylaxis 28w and 34w: best practice (reduces anti-D Ab formation from 1.8% to 0.14%*): however could not be justified in view of supply situation Strategy for self sufficiency: Additional funding to increase anti D plasma collection license minidose 250IU (May 2001) Supplement with imported anti-D, WinRho (Oct 2002) Guideline review 2001: Staged introduction of routine antenatal prophylaxis Education regarding appropriate use © Commonwealth of Australia 2003 *Bowman JM, Chown B, Lewis M et al. Rh-immunization during pregnancy: antenatal prophylaxis. Can Med Assoc J 1978; 118: 623.

Where are we now ?

Graph showing individual state contributions and total trends Stopped recruitment for primary immunisation in 2013 as sufficient supply However within 2 years targets revised again. Now just short of target. Why steady decrease? What to do about it?

The future Careful management of RhD IgG supply Non-invasive fetal blood typing (fetal DNA in maternal circulation) => target RhD IgG to mothers with RhD positive fetuses Continue successful intrauterine management of affected fetuses Intensive phototherapy for affected infants.