HbF-inducing gene therapies for the β-hemoglobinopathies: implications for future pregnancies

The most recent somatic gene therapies strategies for β-hemoglobinopathies - sickle cell disease and β-thalassemia – aim at stable re-expression of high level of fetal hemoglobin (HbF) are transforming the contemporary therapeutic landscape. HbF, expressed during in utero life and physiologically silenced after birth, has a higher affinity for oxygen allowing for transplacental exchange of oxygen. Its persistence at significant levels in the maternal circulation could impair fetal oxygenation during subsequent pregnancies. To anticipate the obstetric risks in this emerging population, we synthesize existing evidence on pregnancy outcomes in women with hereditary persistence of fetal hemoglobin (HPFH)—a naturally occurring model of elevated HbF—to apprehend potential maternal and fetal impacts in individuals having undergone gene therapy for β-hemoglobinopathies. Evidence is very limited. It strongly suggests that moderate HbF levels (10–30%) reduce both maternal and fetal complications in sickle cell disease. However, levels exceeding 50%, as observed after gene editing in β-thalassemia, might blunt the maternal-fetal oxygen affinity gradient and contribute to placental insufficiency and fetal growth restriction. Based on these elements this viewpoint outlines pragmatic adaptation of the current recommendations for antenatal monitoring in pregnancies with supraphysiological level of maternal HbF. As gene-therapies are offered to teenagers and young adults and includes fertility preservation prior to conditioning, obstetricians and hematologists will be requested to manage post-therapy pregnancies in this population. Multidisciplinary guidelines and dedicated registries will be essential to ensure maternal safety and optimize perinatal outcomes within this evolving therapeutic landscape.