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Ali Amid Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada

A longitudinal study on the outcome of intrauterine transfusion in hemoglobin Bart’s hydrops fetalis. Ali Amid Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada On behalf of:

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Ali Amid Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada

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  1. A longitudinal study on the outcome of intrauterine transfusion in hemoglobin Bart’s hydrops fetalis Ali Amid Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada On behalf of: Ali Amid, Laura A Janzen, Catherine I Segbefia, Shiyi Chen, Uma Athale, Karen Charpentier, Manuela Merelles-Pulcini, Gareth Seaward, Edmond N Kelly, Isaac Odame, John S Waye, Melanie Kirby-Allen, Greg Ryan

  2. Introduction • Homozygous α0-thalassemia (hemoglobin Bart’s hydrops fetalis) results from deletion of the duplicated α-globin genes (HBA1 and HBA2) from both copies of chromosome 16p. • Absent production of α-globin chains results in the formation of hemoglobin Bart’s (γ4) in the fetus, instead of fetal hemoglobin (α2γ2). • Hemoglobin Bart’s has an extremely high oxygen affinity, which results in ineffective tissue oxygen delivery. • Progressively severe anemia, tissue hypoxia, and cardiac hypertrophy and dysfunction lead to hydrops fetalis and, frequently, intrauterine fetal demise (IUFD). • Hb Bart’s hydrops fetalis is the most common cause of hydrops in Southeast Asian population Chiu DH and Waye JS, Blood 1998, Amid A et al, Blood 2016

  3. Background • Data on long-term survivors of hemoglobin Bart’s hydrops fetalis has been generally limited to case reports. • An international consortium of Hb Bart’s hydrops fetalis has reported the long-term outcome of 69 survivors, however, the study was not designed to evaluated the effect of intrauterine transfusion. • There is a paucity of data on the effectiveness and ethical aspects of intrauterine transfusion for these patients. • This longitudinal study was designed to evaluate the outcome of intrauterine transfusion in hemoglobin Bart’s hydrops fetalis, providing important information for effective family counselling and therapeutic intervention. Songdej D et al, Blood 2017

  4. Study setting: Ontario, Canada • Ontario is Canada’s most populated province. • Approximately 14 millions • Diverse ethnic population, including many originally from regions with high rates of α-thalassemia mutations. • ~4% Southeast Asia • Has approximately 140,000 births per annum. Statistics Canada, 2015

  5. Data Collection • Genotype of all Hb Bart’s hydrops fetalis cases (fetuses and newborns) diagnosed in Ontario: • From 1989 to 2015, the Provincial Molecular Diagnostic Laboratory at McMaster University. • Data on pregnancy and delivery from the Fetal Medicine Unit at Mount Sinai Hospital, Toronto, the main fetal therapy center in Ontario. • Data on long-term outcome were collected from the all of the four comprehensive thalassemia clinics in the province. • Toronto, Ottawa, Hamilton, London • Data from 24 patients with transfusion-dependent beta-thalassemia (TDT-β) were used as controls for comparison of growth, transfusion-related iron overload and endocrinopathies.

  6. Results: epidemiology and genetics • Ninety-nine affected fetuses were identified, all from singleton pregnancies. • On overage 4-5 affected pregnancies were diagnosed per annum. • 3-4:100,000 pregnancies in Ontario • All patients were of Southeast Asian background. • 1:1000 in pregnancies in Southeast Asian population in Ontario • Identified mutations were as follows: --SEA/--SEA: 88 pregnancies --FIL/--THAI: 9 pregnancies --SEA/--THAI: 1 pregnancy --SEA/--HW: 1 pregnancy

  7. Results: intrauterine intervention • Of the 99 diagnosed pregnancies: • 74 were terminated or resulted in miscarriage • 12 continued to delivery without IUT • 13 received x1-4 IUT • 9 at or before 28 weeks gestation • 4 after 28 weeks gestation • 9 long-term survivors were followed for total of 92.1 patient-years. • Survival rate was 36% in 25 pregnancies resulted in delivery • Survival rate was 69% in those receiving intrauterine transfusion • No patients without IUT survived the first week of life. • Of the 16 deceased neonates: • 15 due to complications of hydrops • 1 due to CMV infection (had IUT) Pregnancies affected: 99 • Terminated or miscarriages: 74 • Diagnosed before termination: 66 • Diagnosed after termination: 8 Continued with pregnancy IUT: 13 No IUT: 12 IUT =<28 wks: 9 IUT >28 wks: 4 none survived 1 survived 8 survived

  8. Results: prenatal • The gestation at first IUT was 18-32 (mean 26) weeks. • The first fetal hemoglobin was 51-80 (mean 70.5) g/L: • There was no correlation between the first fetal hemoglobin concentration and gestational age (r: 0.2649, p=0.45). • Initiation of IUT later than 28 weeks gestation was associated with an increased risk of perinatal mortality (OR: 24.0, 95%-CI: 1.11-518, p=0.042). • Compared to those who were transfused in-utero, babies with no intervention were born earlier (median 30 weeks [range 23-40] vs. 37 weeks [range 31-41], p=0.003).

  9. Results: postnatal • All newborns received transfusion within the first month of life, and survivors has been on chronic transfusion since, except one transplanted patient. • All male newborns had genitourinary abnormalities • Hypospadiasis, undescended testis, micropenis • 5 surviving patients had bone deformities • Absent/deformed digits, rib deformity • Only 3 newborns (all in IUT group) did not have evidence of hydrops at birth. All hydrops-related complication resolved in long term survivors • 3 surviving neonates had portal vein thrombosis

  10. Results: long-term clinical outcome • Patients with homozygous α0-thalassemia developed iron overload and required initiation of iron chelation therapy at an earlier age compared to TDT-β patients. • Ferritin at 12 month of age: 1242 μg/dL(SD 419) vs. 418 μg/dL ( SD 113), p<0.001 • homozygous α0-thalassemia patients had a comparable degree of liver iron concentration while on iron chelation therapy. • LIC: 9.6 mg/g (SD 5.7) vs. 8.6 mg/g (SD 7.9) • Endocrinopathies and short statue were observed more frequently in patients with homozygous α0-thalassemia.

  11. Results: long-term neurocognitive outcome • Five patients underwent neurocognitive assessment and none showed any intellectual impairment. • In three (of 5) patients older than 6 years, MRI studies demonstrated brain changes consistent with “silent” ischemic infarcts.

  12. In Conclusion • In areas with high rate of α0-thalassemia deletions and in high-risk couples (e.g. consanguinity), homozygous α0-thalassemia should be considered in differential diagnosis of hydrops fetalis. • Early diagnosis of affected pregnancies coupled with appropriate counselling provides a basis for informed decision making and future family planning. • Intrauterine transfusion, as well as specialized post-natal care can be associated with improve long-term outcome and should be offered to couples who elect to proceed with pregnancy. • Survivors of Hb Bart’s hydrops fetalis require chronic life-long transfusion, and are at higher risk of transfusion-related and thalassemia-related complications.

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