thalassemia, nursing

Treatment of alpha(0)-thalassemia (--SEA/--SEA) via serial fetal and post-natal transfusions: Can early fetal intervention improve outcomes? Ramen H. Chmait1, Jacquelyn L. Baskin2,3, Susan Carson3, Linda M. Randolph4, Anita Hamilton5

1Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 3Children’s Center for Cancer and Blood Diseases, Children’s Hospital of Los Angeles, Los Angeles, CA, USA, 4Department of Pediatrics, Division of Medical Genetics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 5Children’s Orthopaedic Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Objective and importance: Homozygous Southeast Asian alpha-thalassemia mutation (--SEA/--SEA) results in deletion of all alpha-globin genes (alpha(0)-thalassemia). Since all alpha-globin chains are absent, hemoglobin F cannot be synthesized, and hemoglobin Bart’s becomes the dominant fetal hemoglobin. Hemoglobin Bart’s is a γ tetramer with a very high oxygen affinity, thus oxygen delivery to the tissues is poor. Clinical manifestations include severe fetal anemia, hydrops fetalis, fetal demise, and high risk of neurodevelopmental impairment in the rare survivors. Clinical presentation: A 39-year-old Vietnamese woman presented to our center at 28 0/7 weeks’ gestation with fetal alpha(0)-thalassemia (--SEA/--SEA type deletion) and ultrasound markers suggestive of severe fetal anemia. Intervention: The fetus was treated with four intrauterine transfusions followed by post-natal chronic transfusions. Formal neurodevelopmental testing (Battelle Developmental Inventory, Second Edition) was performed at 18 months of age, and the developmental quotient was 93 (32nd percentile) with all subdomains noted within normal limits, indicating overall intact neurodevelopment. Conclusion: We posit that earlier diagnosis and fetal treatment, prior to clinical findings suggestive of fetal anemia, may improve long-term outcomes by enhancing oxygen delivery to the tissues of the developing fetus.

Keywords: Homozygous alpha-thalassemia, Bart’s hemoglobinopathy, Hydrops fetalis, Intrauterine transfusion

Objective and importance Alpha-thalassemia is a common hereditary hemoglo- binopathy caused by defective production of the alpha-globin chain. The alpha-globin gene cluster con- tains two pairs of genes on chromosome 16. There are over 100 different molecular defects of this gene cluster, and the clinical phenotypes can vary greatly.1

Southeast Asian alpha-thalassemia mutation (--SEA) is one of the most frequent and severe alpha-thalasse- mia mutations. Homozygous --SEA alpha-thalassemia deletion (--SEA/--SEA) results in deletion of all alpha- globin genes (alpha(0)-thalassemia), but the

embryonic genes are spared.2 Since all alpha-globin chains are absent, fetal hemoglobin (hemoglobin F) cannot be synthesized, and hemoglobin Bart’s becomes the dominant form of hemoglobin beginning at ∼8 weeks’ gestation. Hemoglobin Bart’s is a γ tetra- mer with a very high oxygen affinity, thus oxygen delivery to the tissues is poor.3 Affected fetuses usually are either stillborn or die soon after birth. The clinical features of a fetus with alpha(0)-thalasse- mia are severe anemia, extramedullary erythropoiesis, marked hepatosplenomegaly, heart failure, and diffuse edema (hydrops fetalis).2 Survivors have an increased prevalence of neurological or congenital abnormalities (particularly urogenital and limb defects), which has been attributed to disturbed fetal development second- ary to chronic fetal hypoxia.4

Correspondence to: Ramen H. Chmait, Department of Clinical Obstetrics and Gynecology, Pediatrics, and Surgery, Keck School of Medicine, University of Southern California, 1300 North Vermont Avenue, Suite 710, Los Angeles, CA 90027, USA. Email: [email protected]

© W. S. Maney & Son Ltd 2015 DOI 10.1179/1607845414Y.0000000187 Hematology 2015 VOL. 20 NO. 4 217

In contrast to the poor outcomes in untreated alpha(0)-thalassemia, recent case studies describing fetal treatment with serial intrauterine transfusions fol- lowed by aggressive post-natal management via chronic transfusions with chelation therapy or hemato- poietic stem cell transplantation have reported improved survival and long-term neurological out- comes.5,6 Identification of the at-risk fetus prior to the onset of hydrops fetalis can be attained via ultra- sound and pre-natal genetic testing. Ultrasound markers that have been utilized to identify a fetus with alpha(0)-thalassemia include elevated middle cer- ebral artery peak systolic velocities (screen for fetal anemia), placentomegaly, and increased cardiothor- acic ratio.3 Genetic testing can diagnose this condition in the first or early second trimester, well before clini- cal findings become apparent on ultrasound. We posit that earlier diagnosis and fetal treatment, prior to clinical findings suggestive of fetal anemia, may improve long-term outcomes by enhancing oxygen delivery to the tissues of the developing fetus. We describe a well-documented case of fetal

alpha(0)-thalassemia (--SEA/--SEA type deletion) treated with serial intrauterine transfusions and post- natal chronic transfusions, and we explore strategies to improve long-term outcomes in this patient population.

Clinical presentation Pre-natal course A 39-year-old Vietnamese woman presented to our center at 28 0/7 weeks’ gestation with suspected severe fetal anemia due to Bart’s hemoglobinopathy. The patient underwent a genetic amniocentesis at 16 5/7 weeks’ gestation because of a positive first trime- ster screen for trisomy 21, and the results revealed a 46,XY fetal karyotype. At that time, the woman was noted to have a hemoglobin (Hgb) level of 12.8 g/dl and a mean corpuscular volume of 72.5 fl. Laboratory testing of the mother revealed that she was a heterozygous carrier for the Southeast Asian alpha-thalassemia mutation (αα/--SEA). Amniotic fluid cells set aside for thalassemia testing could not be cultured. A second amniocentesis performed at 24 4/7 weeks’ gestation identified the fetus to be homozy- gous for the --SEA alpha-thalassemia deletion (--SEA/--SEA). An initial ultrasound performed at our center at 28

0/7 weeks’ gestation showed a live singleton fetus with an estimated fetal weight of 949 g, which was at the fifth centile. Anatomical examination revealed severe cardiomegaly and a pericardial effusion. There was no evidence of hydrops fetalis. No other structural abnormalities were seen. The amniotic fluid volume was normal (maximum vertical pocket of amniotic fluid measured 4.5 cm). There was placentomegaly,

with a maximum placental depth of 5.1 cm. Doppler interrogation revealed an elevated middle cerebral artery peak systolic velocity of 78.0 cm/second, which was at 2.11 multiples of the median and sugges- tive of severe fetal anemia. Otherwise normal umbili- cal artery, umbilical vein, and ductus venosus waveforms were noted. Fetal echocardiogram con- firmed severe cardiomegaly (cardiothoracic ratio 0.65), pericardial effusion, and increased cardiac output (estimated combined cardiac output of 1030 ml/minute), consistent with fetal heart failure.

The patient was informed that the findings were consistent with fetal growth restriction, high-output cardiac failure, and severe fetal anemia, due to fetal alpha(0)-thalassemia (--SEA/--SEA type deletion). She was informed of the grave prognosis, and that survi- vors have a relatively high rate of neurological and/ or developmental problems. The following manage- ment options were discussed: (1) expectant manage- ment with neonatal comfort-care measures should the fetus survive until delivery; (2) outright delivery; (3) termination of pregnancy; or (4) intrauterine trans- fusions with subsequent post-natal chronic transfu- sions and possible bone marrow transplantation. After consultations with hematology–oncology, gen- etics, cardiology, and neonatology specialists, the patient elected to proceed with serial fetal transfusions.

The patient underwent four uncomplicated umbili- cal vein cordocenteses and intrauterine transfusions at 28 1/7, 30 0/7, 33 0/7, and 36 0/7 weeks’ gestation. The fetal Hgb levels pre- and post-transfusions are shown in Table 1. Hgb electrophoreses performed on the fetal blood sample acquired just prior to the four fetal transfusions and at birth are listed in Table 2. Red blood cell (RBC) phenotyping was performed on the fetal blood sample to diminish risk of alloim- munization and transfusion reactions after birth. A fetal magnetic resonance imaging (MRI) was per- formed at 33 5/7 weeks’ and no fetal intracranial or other structural abnormalities were detected.

The patient presented in labor at 39 1/7 weeks’ ges- tation and delivered vaginally without complication a male infant who weighed 2985 g. Purposeful milking of the umbilical cord was done at delivery to provide the neonate with a blood transfusion from the pla- centa. Apgars of 8 and 9 were assigned. The newborn required continuous positive airway pressure via nasal cannula due to oxygen desaturation and grunting, but he otherwise transitioned well. The baby was transferred to the neonatal intensive care unit (NICU) shortly after birth for further evaluation.

NICU course On physical examination in the NICU, the baby was noted to have a liver edge palpable ∼3–4 cm below the costal margin, but had an otherwise normal

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examination. No dysmorphic features or extremity or genitourinary anomalies were noted. A chest X-ray demonstrated cardiomegaly and mild increase in bronchovascular markings. An echocardiogram revealed mild biventricular hypertrophy and an apical muscular ventricular septal defect. Initial post- natal complete blood count demonstrated Hgb of 18.9 g/dl and hematocrit (Hct) of 59.9%. Hgb electro- phoresis results from the cord blood are shown in Table 2. Arterial blood gas could not be obtained. The neonate remained hemodynamically stable and was weaned to room air and then discharged home on day of life (DOL) #4. A hearing screen was com- pleted, which he passed without difficulty. The Hgb level on discharge was 15.6 g/dl with a Hct 50.3%.

Outpatient care At the initial outpatient clinic visit on DOL #14, the Hgb was 12.5 g/dl and Hct 40.3%. He returned on DOL #28 and the Hgb level decreased to 9.5 g/dl and Hct to 30.7%, at which point the patient received his first post-natal packed RBC (PRBC) transfusion. He continues to receive PRBC transfusions every 3 weeks with an initial goal to maintain the Hgb nadir >10 g/dl. He was noted to have suboptimal growth during the first year of life, so the amount of PRBCs administered was increased to maintain Hgb >10.5 g/dl to optimize growth and development. At 18 months of age, the boy received a total of 26 PRBC transfusions for a total of 2163 cc in his post-natal course, equivalent to close to 300 cc/kg. He has maintained adequate vascular access with peripheral intravenous catheters and has not yet required a central venous catheter for his chronic transfusions. Human leukocyte antigen (HLA) typing of the

patient and his only sibling, a 7-year-old brother

who does not have evidence of alpha-thalassemia, were performed to assess compatibility for a possible matched sibling bone marrow transplant. The brother was not found to be a match.

Future plans The long-term plan for this patient is to continue PRBC transfusions approximately every 3 weeks with adjustments to maintain appropriate Hgb and optimize his growth and development. Considering that transfusional hemosiderosis is a universal compli- cation for patients on long-term chronic transfusions, particularly thalassemia patients with ineffective erythropoiesis, we plan to complete the first MRI to assess iron overload close to 2 years of age with subsequent initiation of chelation therapy. Although considered a crude measurement of iron overload, his elevated ferritin level of 1890 ng/ml indicates that he likely has already begun to accumulate iron.

Developmental assessments During his inpatient and outpatient evaluations, the patient was noted to be developmentally on target. At 6 months of age he was rolling over, sitting with assistance, and laughing responsively. At 9 months, he had already started crawling, pulling to stand, and was babbling and saying mama. Then, by 1 year of age, he was already cruising and saying a few words and within a few months he was taking a few steps on his own. Formal neurodevelopmental testing was performed

at 18 months of age via the Battelle Developmental Inventory, Second Edition (BDI-2).7 The total BDI-2 developmental quotient (DQ) for this patient was 93 (32nd percentile), indicating overall intact neurodeve- lopment. Subdomains all placed within normal limits, and were as follows: communication, including

Table 1 Intrauterine transfusions

GA (weeks) Pre-transfusion

hemoglobin (g/dl) Post-transfusion hemoglobin (g/dl)

Transfusion volume (ml)

Hematocrit of donor PRBC (%)

IUT #1 28 1/7 6.6 11.7 48 86.3 IUT #2 30 0/7 10.3 13.9 45 75.7 IUT #3 33 0/7 9.6 14.9 85 54.0 IUT #4 36 0/7 11.2 14.2 70 92.2

GA, gestational age; PRBC, packed red blood cells; IUT, intrauterine transfusion.

Table 2 Fetal Hgb electrophoresis obtained prior to fetal transfusions and at birth

GA (weeks) Hemoglobin A (%) Hemoglobin A2 (%) Hemoglobin F (%) Hemoglobin Bart’s (%)

IUT #1 28 1/7 0.0 0.0 0.0 100.0 IUT #2 30 0/7 32.5 0.8 0.0 66.7 IUT #3 33 0/7 57.7 1.3 0.0 41.0 IUT #4 36 0/7 74.0 1.6 0.0 24.4 Birth 39 1/7 85.1 2.6 1.1 11.2

GA, gestational age; IUT, intrauterine transfusion.

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receptive and expressive language (DQ = 92; 30th per- centile), motor (DQ = 103; 58th percentile), perso- nal–social (DQ = 95; 37th percentile), and adaptive (DQ = 100; 50th percentile). The cognitive subdomain placed in the low average range (DQ = 84; 14th percentile), in large part due to difficulty tolerating structured play tasks, distractibility, and behavioral non-compliance, rather than frank neurodevelopmen- tal delays. In addition, the parent reported low exposure to structured play/learning tasks (e.g. books, puzzles, stacking toys), which likely contribu- ted to a lower than expected cognitive performance. Qualitatively, the patient was age-appropriately

alert, highly energetic, interpersonally engaged, and explored his environment. When motivated he was focused, persistent, and found age-appropriate sol- utions to problems (e.g. opening the door, finding a hidden object, using a neat pincer to place a small object in a bottle, holding the paper down with his hand while scribbling). In sum, the patient demon- strated intact neurodevelopment with four out of five subdomains placing in the average range. Low average cognitive performance was likely due to environmental factors (e.g. parenting style and lack of exposure to learning tasks such as books and puzzles) rather than frank neurodevelopmental delay.

Conclusion In this case, we documented rapid resolution of fetal anemia after intrauterine transfusion (Table 1). However, as shown in Table 2, which depicts the Hgb electrophoreses obtained prior to each of the four fetal transfusions and at birth, reduction of the concentration of Bart’s Hgb was a more gradual process. Both resolution of anemia and reduction of Bart’s Hgb content are important for optimal fetal growth and development, for both measures serve to increase oxygen delivery to the fetus. We believe that early initiation of intrauterine transfusions, even before the clinical findings of fetal anemia arise, may improve long-term outcomes. Replacement of hemo- globin Bart’s with hemoglobin A may serve to opti- mize oxygen delivery to the fetus due to the more favorable oxygen dissociation curve of the transfused adult Hgb.3,5 With improvements in genetic testing and the relatively low procedure-related risks of fetal transfusion in the modern era of high-resolution ultra- sound, we believe that there is a strong argument for early fetal diagnosis and treatment of alpha(0)- thalassemia. Formal neurodevelopmental testing was performed

in this patient at 18 months of age via the BDI-2 test. The DQ was 93 (32nd percentile) with all subdo- mains noted within normal limits, indicating overall intact neurodevelopment. The cognitive subdomain was in the low average range (DQ = 84; 14th

percentile), but this was attributed to distractibility and behavioral non-compliance, rather than frank neurodevelopmental delays. These findings are in line with other cases that describe neurodevelopmental outcomes after serial intrauterine transfusions fol- lowed by aggressive post-natal therapy.6 It is well known that the risk of major neurological injury in alpha(0)-thalassemia survivors not treated with fetal transfusion is high, with one case series and literature review reporting this risk at 46% (5 of 11).4 Thus, it is provocative to posit that early initiation of fetal trans- fusions may improve neurodevelopmental outcomes. However, it is important to note that hemoglobin Bart’s becomes the dominant form of Hgb beginning at ∼8 weeks’ gestation and that typically fetal transfu- sions are initiated in the latter half of the second trime- ster due to technical considerations, well after completion of fetal organogenesis. Therefore, although there is overall improvement in outcomes, there is no doubt that the survivors of fetal transfu- sions remain at some risk for neurodevelopmental impairment or development of congenital anomalies, and prospective patients should be counseled accordingly.

Furthermore, post-natal treatments may also impact long-term outcomes. Studies of beta-thalassemia major patients have demonstrated that, although sur- vival has improved for these patients, health-related quality of life (HRQOL) remains an important issue with overall scores lower than those compared with the general population.8 Lower iron burden, improved adherence, earlier initiation of chelation, and non- invasive methods to monitor iron burden have improved both life expectancy and HRQOL.9 One study comparing HRQOL outcomes in beta-thalasse- mia patients from the year 2001 and then re-assessed in 2009 found that HRQOL scores were improved in 2009, particularly in the areas of mental health.9 La Nasa et al.10 specifically looked at long-term HRQOL outcomes for patients that underwent a hematopoietic stem cell transplant (HSCT) and found that even though 74% of patients had at least one co-morbidity, the total population had compar- able HRQOL scores to the general public, aside from slightly lower scores on general health, and higher scores than other thalassemia patients treated with chronic PRBC transfusions. Although patients with thalassemia major may have lower HRQOL when compared with the general public due to their chronic condition, advances in medical therapy and improved supportive care measures will have a positive impact on patients’ long-term survival as well as their HRQOL. Thus, parents should be counseled regard- ing the potentially life-long challenges of post-natal therapy. The long-term therapy for patients with tha- lassemia major disorders consists of regularly

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scheduled PRBC transfusions combined with chela- tion therapy for resulting hemosiderosis versus HSCT. Chronic PRBC transfusions are required initially for

all patients with thalassemia major and are life-long therapy for those that do not undergo a transplant. However, there are various risk associated with chronic PRBC transfusions, including exposure to blood borne infections, transfusion reactions, allo- and autoimmunization, and hemosiderosis.11

Iron overload is the most common complication associated with chronic PRBC transfusions. Iron over- load can lead to multi-organ damage including cirrho- sis of the liver, diabetes due to insulin resistance secondary to the total body iron burden and insulin deficiency secondary to pancreatic iron, cardiomyopa- thy and arrhythmia from cardiac iron, and multiple endocrinopathies related to iron loading into the pitu- itary gland.12–14 With the introduction of chelation therapy, patient survival has improved, now approach- ing normal life expectancy. New chelation agents have been introduced recently that may be administered orally and can be tailored to the patient, depending on the level and location of hemosiderosis, patient’s individual risk for known adverse effects, and feasi- bility for long-term adherence. The risks and benefits of chelation at an early age must be considered. Considering only a small number of children with alpha(0)-thalassemia survive, there are no data to determine optimal timing of initiation of chelation therapy in this group of patients. The literature addres- sing time to initiate chelation therapy, including drug safety testing, is largely based on beta-thalassemia patients in whom PRBC transfusions, and sub- sequently iron overload, develops at a later age. For this reason, chelation trials have not addressed the safety or appropriate dosages of these medications in children <2 years of age and are not currently approved for this population. Although it is likely that patients like the one described in this report have already developed hemosiderosis by 2 years of age, the benefit of early chelation therapy is not well established. Children with decreased erythropoiesis, such as Diamond–Blackfan anemia (DBA), develop iron overload faster than those with ineffective ery- thropoiesis, such as those with thalassemia, yet even those with DBA have not been shown to develop sig- nificant organ damage, such as pancreatic or cardiac iron, at such a young age.15 Moreover, the literature demonstrating the potentially irreversible impairment of neurological development in children with iron deficiency at this age raises the concern that early che- lation poses this potential risk and must be considered when making this decision.16 For these reasons, it was decided in this case to wait until closer to 2 years of age to evaluate for iron overload and initiate chelation therapy.

Post-natal HSCT is another option for these patients, although there are significant associated risks such as infection, marrow aplasia due to graft rejection, and acute or chronic graft-versus-host disease (GVHD). Optimal outcomes of this treatment modality depend on the absence of patient-related risk factors that impact long-term outcomes such as extent of hepatomegaly, portal fibrosis, and adequacy of iron chelation.17,18 The risk of specific transplant-related outcomes are also dependent on the donor type. The majority of clinical experience comes from beta-tha- lassemia major patients. Matched related donor bone marrow HSCT yield overall survival (OS) >90% and beta-thalassemia-free survival >80%, while recent reports for matched unrelated donor bone marrow HSCT have OS at 79% and thalassemia-free survival 66%.19 Matched related cord blood HSCT are being utilized more frequently and now demonstrate improved results.20

Although rare, there are four case reports of HSCT in patients with 4-gene alpha-thalassemia, including two matched related donors, one related 5/6 cord blood, and one unrelated 5/6 cord blood transplant.21–24 Three of the four patients did not receive intrauterine PRBC, all of whom were born prematurely and with some level of hydrops fetalis.22–24 One patient did receive four intrauterine PRBC transfusions and was born full term without complications.21 HSCT occurred between 20 and 44 months of age, were well tolerated without evidence of significant GVHD or infection, although two patients developed stable mixed chimerism, but remain disease free. These reports indicate that, as demonstrated in the beta-thalassemia population, HSCT can be an option if the appropriate donor is available. When discussing transplant with patients with thalassemia and their family, the patient’s clinical condition and types of stem cell donors available must be considered when determining optimal long-term management. HLA typing of our patient’s only sibling revealed that he was not an appropriate match for sibling bone marrow transplantation. In summary, alpha(0)-thalassemia, once considered

a lethal condition, can be successfully managed with favorable outcomes. Strategies to optimize long-term outcomes include early aggressive intrauterine transfu- sions, prior to the clinical manifestations of fetal anemia, with the goal to replace hemoglobin Bart’s and thereby improving oxygen delivery. The first fetal blood sample extracted may be sent to the blood bank to plan future treatment (i.e. cross- match, possible bone marrow transplantation). Post- natal management via a multidisciplinary team to weigh the risks and benefits of the various treatment modalities in a case-by-case basis is important.

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Disclaimer statements Contributors All authors have made substantial con- tributions to the conception and design of the manu- script, as well as the writing and approval of the final version of the manuscript.

Funding None.

Conflicts of interest None.

Ethics approval Institutional Review Board approval was received by the University of Southern California HSIRB.

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