1. Thalassemia in Pregnancy Bassem Gerges 2 nd of September 2014

2. The Basics - Haemoglobin Main function to carry O2 to tissues and to return CO2 from the tissues to the lungs Three types of haemoglobin  Haemoglobin A (dominant after the ages of 3-6 months)  Haemoglobin F  Haemoglobin A 2 Normally  4 α-globin chains mapped to short arm of Chromosome 16  2 β-globin chains mapped to short arm of Chromosome 11

4. α-Thalassemia Caused by deletions of one or more of the four α-globin genes α-Thalassemia trait is either α + (three normal α-genes) or α 0 (two normal α- genes)  Usually asymptomatic  Important to identify as may become anaemic in pregnancy α-Thalassemia major results if both parents have α 0 and there are no functional α-genes (Hb Barts)  Incompatible with life  Foetus becomes severely hydropic

6. α-Thalassemia (cont’d) Haemoglobin H disease  Three α-gene deletions  Clinically mild disease  May require occasional transfusion of RBC  Not considered “transfusion dependent”

7. β-Thalassemia Arise out of mutations in the β-globin genes  Decreased (β + ) genes  Absent (β 0 ) genes  As with α-thalassemia, in β-thalassemia the β-globin chains are structurally normal but quantatively reduced β-Thalassemia trait (minor)  Generally asymptomatic  May become anaemic in pregnancy  Clinically manifestations  Minimal hypochromic microcytic anaemia  Increase in Haemoglobin A 2 (α 2 δ 2 )

9. β-Thalassemia major Inheritance of a defective β-globin gene from each parent Severe anaemia becomes apparent at 3-6 months after birth with the switch to β-chain production Fatal within a few years without regular transfusions Children can now survive to the second or third decade Also known as Mediterranean anaemia or Cooley anaemia

10. β-Thalassemia major (cont’d) Clinical features  Marked anaemia from  Modest decrease in haemoglobin synthesis  Marked shortening of red cell life span due to aggregation of insoluble excess α-chains  Ineffective erythropoiesis  Relative folate deficiency  Marked hepatic- and splenomegaly  Excessive red cell destruction  Extramedullary haemopoiesis  Iron overload from repetitive transfusions  Distortion of skull, facial bones, and long bones because of erythroid marrow expansion

11. β-Thalassemia major (cont’d) Clinical features (cont’d)  Thalassemic red cell morphology  Marked microcytosis, hypochromia, target cells and extensive changes in size and shape  Increased Haemoglobin F (α 2 γ 2 )  Generalised haemosiderosis  Chronic haemolysis  Ineffective erythropoiesis  Repeated transfusions

14. Screening for Thalassemia SOGC  FBC and HbEPG for all women from an ethnic background at increased risk  Individuals with an MCV < 80 fL or MCH < 27 pg can have α- and/or β-thalassemia and/or iron deficiency anaemia  β-thalassemia trait can be reliably diagnosed by haemoglobin electrophoresis, with HbA2 and HbF quantitation  Patients with β-thalassemia trait have an elevated HbA2, i.e., > 3.5%  In patients with a low MCV, but with a normal Hb EPG and HbA2 and HbF quantitation, the differential diagnosis includes iron deficiency anaemia and α-thalassemia.  A serum ferritin and a smear to screen for the H bodies of α-thalassemia are therefore required  HbEPG will allow identification of Hb variants, such as HbS, C, D, and E  The finding of any abnormality requires screening of the partner  FBC, smear for H bodies, Hb EPG, and HbA2 and HbF quantitation  If both partners are found to be carriers of haemoglobin mutations (i.e., any combination of thalassemias and Hb variants), they should be referred for genetic counselling, ideally in the pre-conception period, or as early as possible in the pregnancy

17. Prenatal Diagnosis Prenatal diagnosis by DNA analysis of chorionic villi or amniocytes should be offered to all carrier couples at risk For couples at risk of severe α-thalassemia who decline invasive prenatal diagnosis, or who present after 20 weeks of gestation, ultrasound assessments in a tertiary centre to determine the foetal cardiothoracic ratio could be offered  Shown to be a reliable mean of identification of a foetus with Hb Bart’s hydrops fetalis  A cardiothoracic ratio level equal to or greater than 0.5 identifies all affected pregnancies and has a false positive rate of 8% The finding of hydrops fetalis on ultrasound in the second or third trimester in women with an ethnic background that has an increased risk of α–thalassemia should prompt immediate investigation of the pregnant patient and her partner to determine their carrier status for α- thalassemia.

18. Management Preimplantation genetic diagnosis with IVF Iron chelation therapy with desferrioxamine used by women with β- thalassemia should be ceased Check and optimise any endocrine and cardiac dysfunction prenatally Need iron and folate oral supplements throughout pregnancy  Should not be given parenteral iron  Consider IM folate if not responding  Transfusion may be required prior to delivery Prenatal Diagnosis Continuation vs Termination of Pregnancy

19. References Handbook of Obstetric Medicine, Catherine Nelson-Piercy SOGC Carrier Screening for Thalassemia and Hemoglobinopathies in Canada Essential Haematology, AV Hoffbrand, JE Pettit, PAH Moss Pathology, Board Review Series www.uptodate.com

20. Thank you