TO THE EDITOR:
α thalassemia is one of the most common single-gene disorders, with a 5% carrier rate globally1 and nearly 40% carrier rate in endemic regions of South East Asia, India, and the Mediterranean.2 This carrier rate results in a high incidence of newborns with severe α thalassemia: for example, a recent report estimates that there are thousands of affected pregnancies per year in Thailand.3 Importantly, given the increased population of people of South East Asian ancestry in North America, severe α thalassemia represents an important and growing public health issue.4 Newborn screening records in California, where there has been a 2000% increase in immigration from Asia in the past 30 years,5 indicate that the prevalence of patients with a clinically significant α thalassemia diagnosis is 9.6 births in 100 000.6
α thalassemia disease severity depends on the number of affected α globin genes.1 The 4-gene deletion results in α thalassemia major (ATM), which has the most severe presentation and typically manifests in utero. Affected fetuses are usually identified because of the clinical finding of hydrops fetalis (abnormal fluid accumulations identified by ultrasonography) that occurs secondary to severe hypoxia. If untreated, hydrops fetalis usually results in fetal demise and can lead to maternal complications such as preeclampsia or mirror syndrome.7
Historically, a family’s options after a prenatal diagnosis of ATM have been limited to either termination of pregnancy or close surveillance with an expectation of fetal loss.8 However, there are accumulating data from a patient registry,9 case reports,10 and case series11-13 regarding outcomes of patients with ATM who survive to birth. Predictably, when in utero transfusions (IUTs) are performed, there is evidence that this therapy can improve oxygenation, reverse hydrops fetalis, and allow survival to birth, usually at or near term.11-13 The prenatal cardiac findings secondary to anemia resolve with transfusions. Importantly, at follow-up, these series have reported that patients who have received IUTs can have normal or near-normal neurologic outcomes.11-13 Survivors with ATM can have significant medical needs: after birth, the management of patients with ATM is similar to those with β thalassemia major, in that they require monthly transfusions to treat the underlying anemia. A hematopoietic stem cell transplantation, if available, can be curative. In addition, male fetuses with ATM often develop hypospadias,14 which can be corrected with surgery.
Despite the emerging evidence for favorable outcomes after fetal therapy for ATM, there is a reluctance in the medical community to offer serial IUTs as an option to expectant parents, often because of concerns that this will result in the birth of a child with a severe, debilitating disease. However, IUT has been routinely performed since 1963 to treat alloimmunization, with an excellent safety profile and has demonstrated minimal risks to the fetus and mother. Despite this experience, parents of fetuses with ATM are usually neither offered this treatment option nor counseled regarding the possibility of improved postnatal outcomes. In other words, families are not provided a full range of decision-making options. There is, in contrast, widespread acceptance of advanced fetal surgeries for several severe conditions that have a similar or more severe postnatal phenotype compared with ATM. For example, there are now numerous interventions for fetuses with spina bifida,15 monochorionic twin complications, sacrococcygeal tumors, bladder outlet obstruction,16 and congenital diaphragmatic hernia,17 many of which result in the birth of a child with a severe disease requiring chronic medical care. ATM could be listed among the conditions for which there is now a life-saving therapy when a prenatal diagnosis is made.
On 8 and 9 January 2021, we convened an international conference (https://conference.globalcastmd.com/ucsf-alpha-thalassemia-major/archive) to review existing knowledge regarding the prenatal screening, perinatal care, and maternal and childhood outcomes of patients with ATM, and a group of stakeholders discussed the desirability of changing the current paradigm of prenatal counseling for this disease. Participants included several families whose children survived in utero transfusions and are now thriving, as well as physicians (perinatologists, neonatologists, pediatric hematologists), genetic counselors, bioethics scholars, patient advocates, and researchers. Here, we outline several points regarding the management of patients with ATM on which our team of prenatal and postnatal experts have reached a consensus. We believe that this outline provides important points to consider for creating best practice guidelines for in utero treatment of ATM.
Couples who are at risk for offspring affected with ATM (those in which both parents are carriers for a 2-gene deletion in cis) should be counseled regarding the risks for this condition and the availability of prenatal screening to determine carrier status. Universal screening, including hemoglobin and red cell indices (mean corpuscular volume) in the preconception or early prenatal period is recommended by the American College of Obstetricians and Gynecologists. Women who are at risk of being carriers for ATM can be identified by a low mean corpuscular volume (<70 fL) on routine complete blood count analysis. Importantly, because red cell indices may fail to identify all carriers, molecular based screening should be pursued in high-risk populations to definitively identify α thalassemia carrier status.18 Notably, hemoglobin electrophoresis and high-performance liquid chromatography tests are unable to identify α thalassemia carriers: although prospective parents should be offered these tests to rule out β thalassemia deletions, they should also be tested for α thalassemia mutations using molecular genetic testing.
If both parents are carriers of ATM, they should be thoroughly counseled about the implications of this diagnosis. This counseling should include the etiology, clinical manifestations, prognosis, and the full range of long-term outcomes, depending on the expected severity of disease based on number of genes affected. Collaborative education (including consultation with pediatric hematologist who is familiar with the management of patients with thalassemia) may be valuable for these families for reproductive planning. Prospective parents should be informed of the option of preimplantation genetic testing for monogenetic conditions of embryos to prevent a pregnancy with ATM. Recognition of the limitations of preimplantation genetic testing19 and need for confirmatory prenatal diagnostic testing20 should be discussed. Patients who are already pregnant should be offered early prenatal diagnosis (via chorionic villus sampling or amniocentesis) to allow for informed decision making about the pregnancy.
The finding of hydrops fetalis in the setting of a pregnancy at risk for ATM because of the parents’ known carrier status is indicative of fetal ATM in most cases. In this situation, the diagnosis should be confirmed as quickly as possible so that parents can be counseled and intervention, if desired by the family, can be implemented. We recommend offering a percutaneous umbilical cord blood sampling with hemoglobin electrophoresis to measure the levels of γ-globin tetramers (ie, Hb Bart’s) to confirm the diagnosis. If the family wishes to pursue intervention, an initial IUT can be performed while awaiting the diagnosis. This strategy avoids the longer turnaround time for amniocentesis results before initiating fetal therapy.
In a pregnancy with a confirmed diagnosis of ATM, nondirective counseling should include the option of expectant management, pregnancy termination, or fetal therapy with IUTs. Parents should also be educated regarding options for a future pregnancy, including preimplantation genetic testing. They should be offered the opportunity to consult with a pediatric hematologist (particularly with one who cares for patients with α thalassemia) to understand the long-term outcomes, prognosis, and the requirements of postnatal and childhood management. If the family elects to pursue IUTs, they should be referred to a center with expertise in this technique if it is not available locally. Given risks for severe maternal complications in the setting of untreated hydrops fetalis,21 expectant management should be discouraged and, if pursued, patients should be monitored closely.
For patients electing to proceed with fetal therapy, IUTs should begin as soon as technically possible (currently 18 weeks at most fetal treatment centers) to minimize long-term impact from fetal hypoxia. The protocol for IUTs is similar to standard protocols for alloimmunization.22
Delivery should be planned at a tertiary care center with availability of perinatology, pediatric hematology, and neonatology teams.
After birth, patients can be treated using guidelines similar to those followed for patients with transfusion-dependent thalassemia,23 including chronic transfusions and iron chelation. Hematopoietic stem cell transplantation, when available and desired by parents, presents the possibility of a definitive cure.
Although health care resources are different in each country and even unique to each patient, it is important to discuss the need for resources to enable chronic medical care with affected families.
Patient advocacy organizations such as Cooley’s Anemia Foundation (in the United States) and Thalassemia International Federation (for patients worldwide) can be valuable resources for linking families to each other and to expert physicians locally and for providing educational materials.
Sharing patient data with an international registry (www.clinicaltrials.gov NCT04872179) will improve understanding of the disease, enable the creation of guidelines for best practices for pre- and postnatal care, and provide valuable information to families regarding long-term outcomes.
A strong consensus emerged among the multidisciplinary attendees at this international conference: ATM should no longer be considered universally fatal. Although decision making during pregnancy is complex and personal, and the availability of medical care varies globally, parents should be offered nondirective counseling regarding all options, including that of fetal therapy with IUTs. Perinatologists with expertise in performing IUTs for other conditions can offer this therapy in close collaboration with pediatric hematologists. After birth, patients can be treated with chronic transfusions or stem cell transplant. Given immigration patterns from regions with a high carrier frequency, there is a growing population of families at risk for ATM in North America and beyond. Recognition of the specific needs for these patients is critical in delivering optimal care. In addition to clinical resources, connecting families within the α thalassemia community via patient advocacy groups will be valuable in helping with informed decision-making.
Acknowledgments: The conference at which this consensus was discussed was funded by a grant from the California Institute for Regeneration Medicine to T.C.M. and funds from the University of California San Francisco Center for Maternal-Fetal Precision Medicine.
Contribution: T.C.M. conceived the project and wrote the paper with input from all authors; and A.A., M.A., C.B., S.G., J.G., R.L.K., S.K., M.K-A., B.A.K., W.K., A.L., B.R.L., M.E.N., K.K.O., T.P., M.R., M.S., A.T., J.S.W., and E.V. participated in consensus discussions and contributed to writing of the manuscript.
Conflict-of-interest disclosure: T.C.M. is on the Scientific Advisory Board of Acrigen.
Correspondence: Tippi C. MacKenzie, Department of Surgery, UCSF, 550 16th St, Box 0570, San Francisco, CA 94143-0570; e-mail: Tippi.firstname.lastname@example.org.