The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry

Abstract

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally and 11 were diagnosed postnatally: all 11 spontaneous survivors' genotypes had preserved embryonic zeta globin. We compared three groups of patients; Group 1 were prenatally diagnosed and alive at hospital discharge (n=14), Group 2 were prenatally diagnosed and deceased perinatally (n=5), Group 3 were postnatally diagnosed and alive at hospital discharge (n=11). Group 1 had better outcomes than Groups 2 and 3 in resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation correlated with higher neurodevelopmental (Vineland-3) scores (r= -0.72, P=0.02). Preterm delivery after IUT was seen in 3/16 (19%) of patients who continued their pregnancy. When we combined our data with those from two published series, patients who received ≥2 IUTs had better outcomes than those with 0-1 IUT, including resolution of hydrops, delivery ≥34 weeks' gestation, and 5-minute Apgar scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT versus 5/13 of the 0-1 IUT group (OR 2.74; P=0.01). Thus, fetal transfusions enable survival of patients with ATM with normal neurodevelopment even in patients presenting with hydrops. Non-directive prenatal counseling of expectant parents should include the option of IUTs.

Dual α-globin and truncated EPO receptor knockin restores hemoglobin production in α-thalassemia-derived red blood cells

“…Moreover, the high expression of ζ-globin found in αTM cells hints at a possible compensatory mechanism for the loss of α-globin in the cell. These findings support the hypothesis that the presence of ζ-globin in patients with α-globin deletions may be protective, as spontaneous survivors of αTM without an in utero transfusion tend not to have deletions that extend into the ζ-globin region 4 . While therapeutic approaches have been developed for β-thalassemia to increase HbF by phenocopying hereditary persistence of fetal hemoglobin (HPFH), either by negating the erythroid enhancer of BCL11A or inducing mutations in the γ-globin promoters, an analogous genome editing strategy has not yet been developed for α-thalassemia.…”

How do we perform intrauterine transfusions?

“…5,8,26 In the case of alpha thalassemia major, which is often fatal in utero due to severe hydrops, antenatal diagnosis and IUT have resulted in some surviving patients, but eventual long-term survival is dependent on hematopoietic stem cell transplantation. 3…”

“…Additionally, IUT has been used to treat inherited conditions such as thalassemias, 23 hemoglobinopathies, 24 and erythrocyte membrane 25 or enzyme defects 5,8,26 . In the case of alpha thalassemia major, which is often fatal in utero due to severe hydrops, antenatal diagnosis and IUT have resulted in some surviving patients, but eventual long‐term survival is dependent on hematopoietic stem cell transplantation 3 …”

“…IUT for fetal anemia leads to improved outcomes 2,3 ; however, it is an invasive and technically challenging procedure with specialized blood component requirements. When performed by an experienced team, fetal survival following IUT is reportedly high with survival rates reaching up to 97% when performed for RhD alloimmunization 2 .…”

“…metabolism, fetomaternal hemorrhage (FMH), aneuploidy, vascular fetal tumors, or twin anemia polycythemia sequence (TAPS) are important considerations in the differential diagnosis. 1 IUT for fetal anemia leads to improved outcomes 2,3 ; however, it is an invasive and technically challenging procedure with specialized blood component requirements. When performed by an experienced team, fetal survival following IUT is reportedly high with survival rates reaching up to 97% when performed for RhD alloimmunization.…”