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Public health issues in the thalassemic syndromes

Public health issues in the thalassemic syndromes
Author:
Emanuele Angelucci, MD
Section Editor:
William C Mentzer, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Feb 2022. | This topic last updated: Jun 10, 2021.

INTRODUCTION — Beta thalassemia occurs in the Mediterranean littoral and all over Southeast Asia (Burma, Thailand, Cambodia, Vietnam, China, Malaysia, Indonesia, and the Philippines). Alpha thalassemia is even more common, occurring with high frequency throughout all tropical and subtropical regions, including most of Southeast Asia, the Mediterranean area, the Indian subcontinent, the Middle East, and Africa [1,2].

Thalassemia is one the most widespread diseases worldwide and represents one of the most dramatic causes of disparities comparing industrialized and developing countries. An estimate by the Thalassemia International Federation (TIF) reports that fewer than 10 percent of global patient communities in the developing world can access the optimal standard of care [3].

Some variants of thalassemia (hydrops fetalis with hemoglobin Barts) are often incompatible with life [4]; others (transfusion-dependent beta thalassemia) are associated with lifelong transfusion-dependent anemia, short stature, facial abnormalities, delayed or absent puberty, and attendant stigmas and psychosocial problems [5,6].

Of major public health importance, individuals with one of the various forms of thalassemia trait may be entirely asymptomatic and unaware of their diagnosis. When they have children with an individual with the same type of genetic variant, the disorder is propagated within these communities. (See "Diagnosis of thalassemia (adults and children)".)

SEVERE THALASSEMIA IN THE DEVELOPED WORLD — An interesting anecdote illustrates our changing perceptions about these disorders. Thalassemia was not diagnosed in Cyprus before 1944 [1]. After World War II, following improvements in public health along with malarial eradication programs, it became apparent that there was a newly recognized but common hypochromic microcytic anemia in children not due to iron deficiency (ie, severe beta thalassemia) [5]. It was quickly realized that, for example, the cost of red blood cell transfusions and chelation therapy per year for a patient with beta thalassemia major exceeded by three to four orders of magnitude the per capita funds available for health care in that country, as well as in much of the developing world.

By 1970, it was projected that, if this disease was not controlled, by the year 2000 the cost of treatment of these children would consume the entire health care budget of Cyprus and require all of the blood that the island could supply, even supposing that 40 percent of the adults would enlist as regular blood donors.

In 2017, it was estimated that the direct costs for treating an individual with transfusion-dependent thalassemia in Italy would be approximately 30,000 USD annually [7]. The prevalence of thalassemia in Italy was estimated at approximately 6500 transfusion-dependent and 6000 non-transfusion-dependent patients. Thus, the management of thalassemia requires a significant use of public health resources, with a total annual direct cost of approximately 287 million Euros. In Turkey, a similar analysis showed a direct cost estimate of almost 15,000 United States (US) dollars for transfusion-dependent patients and slightly more than 9000 US dollars for non-transfusion-dependent patients [8]. The prevalence of thalassemia in Turkey was estimated at approximately 4000 transfusion-dependent and 4000 non-transfusion-dependent patients, allowing for a total annual direct cost of approximately 95,000,000 US dollars.

In the past, in many of the underdeveloped nations, at a time when the infant mortality rate was above 50/1000 births, affected countries devoted their public health efforts to controlling neonatal infectious diseases and malnutrition. Thus, of the well over 300,000 infants with major forms of severe hemoglobin disorders, including the thalassemias, who were born every year, many died untreated or even undiagnosed [5]. However, when the infant mortality rate fell below 40/1000, genetic diseases such as the thalassemias "emerged," along with a demand for appropriate medical services [5], as occurred in Cyprus.

Before 1980, hemoglobin E (HbE) was not recognized in California [9]. Since the California population includes approximately 10 percent Asian Americans, the number of children born with thalassemia has been increasing. As a result, the number of births in California of children with homozygous HbE disease now exceeds the number of births of children with sickle cell disease. In addition, there are now 11 new cases of HbE/beta thalassemia per year, as well as 30 new cases per year of HbH disease (severe alpha thalassemia) [9,10]. Other examples include:

In the United Kingdom (UK), patients with severe HbE/beta thalassemia are mostly of Bengali or Southeast Asian ancestry [11].

A 1998 lead article in the journal "Blood" dealt with an emerging health care problem due to an increased frequency of stillbirths secondary to severe alpha thalassemia (ie, hydrops fetalis with hemoglobin Bart's) [4]. The article came not from China, Singapore, or Hong Kong, where this syndrome had been well described, but from Ontario, Canada [4]. Similar experience from Boston, Massachusetts has been reported [12].

The demographics in these three countries (UK, Canada, United States) have obviously changed [13,14]; simple arithmetic indicates that many patients with thalassemia have not been diagnosed and/or appropriately treated, and that there is clearly a need to improve community education programs, as well as opportunities for genetic and prenatal counseling.

With increasing population movements, combinations of the various thalassemias and hemoglobinopathies are expected to increase. Towards that end, interactions between "source" areas (ie, those with a high prevalence of alpha thalassemia and substantial emigration) and "sink" areas (ie, those with substantial immigration from source areas) have developed [2]. Examples include collaborations between the Philippines and California and between Sri Lanka and the UK [15,16].

An emerging problem particularly seen in southern Europe is that related to immigration. In underdeveloped countries or in countries with ongoing war, thalassemia induces patients to escape their countries and to live in the countries of arrival, sometimes without legal citizenship status or legal protections. This situation prevents access to possible treatments unless in conditions of extreme emergency, when the clinical situation is not recoverable, as the key to clinical success is the regularity and completeness of medical treatment.

EFFECTIVE CONTROL OF THALASSEMIA — Control of thalassemia requires treatment of the individual patient as well as a community-based educational effort to increase awareness of this problem.

Individual patients — Other than the use of transfusion and general supportive care, there is no effective treatment for the vast majority of individuals with severe forms of alpha thalassemia. In addition, the hemoglobin Bart's hydrops fetalis syndrome, which is almost universally fatal for the fetus or newborn, is often accompanied by a variety of maternal complications, which may be fatal. Accordingly, programs for prevention of these disorders, and early detection during pregnancy, assume major importance [2,17].

For individual patients with beta thalassemia major, appropriate treatment includes all of the following (see "Management of thalassemia") [1,5,18,19]:

Lifelong red cell transfusions

Control of the blood supply to avoid transfusing hepatitis and HIV

Chelation programs to minimize transfusional iron overload

Prompt treatment of all infections

Treatment of endocrine complications related to iron overload, including hormone supplementation to allow normal puberty and growth

Splenectomy when and if hypersplenism occurs, particularly in resource-limited countries

Control of osteoporosis

Hematopoietic cell transplantation may be appropriate for selected individuals (see 'Hematopoietic cell transplantation' below). Future options may include use of gene therapy that takes advantage of molecular methods such as CRISPR technology and lentiviral vectors to correct thalassemic defects and/or restore normal levels of beta globin production. (See "Genetics: Glossary of terms", section on 'Genome editing' and "Management of thalassemia", section on 'Gene therapy and other stem cell modifications'.)

The prohibitive cost makes it likely that these methods will be limited to a few cases confined to academic medical centers in the world.

Hematopoietic cell transplantation — If the patient with transfusion-dependent beta thalassemia has an HLA-matched sibling hematopoietic cell donor (approximately 30 percent of patients), lives in a resource-rich country, and/or has the financial resources, an allogeneic hematopoietic cell transplantation (HCT) is essentially curative in >80 percent of such patients. (See "Hematopoietic cell transplantation for transfusion-dependent thalassemia".)

According to a 2012 analysis, HCT is likely to be cost-effective compared with standard medical care [20]. If haploidentical HCT is successful as demonstrated in a 2020 study, it would be possible in the wealthier countries to extend transplantation to haploidentical donors [21]. (See "Hematopoietic cell transplantation for transfusion-dependent thalassemia", section on 'Haploidentical donor'.)

However, this is not a solution for most of the developing world. Unrelated donor HCT has also been used in severely affected adult patients, but only if the potential candidates are rigidly screened and fully informed about the risks of this procedure [22]. (See "Hematopoietic cell transplantation for transfusion-dependent thalassemia", section on 'Matched unrelated donor'.)

Improved diagnostic and screening methods — The underlying cause of the defective and deficient globin chain synthesis in the thalassemias has been explored. For the beta thalassemias, most are problems in gene transcription, while for the alpha thalassemias, gene deletions are the usual cause. Using reliable probes, it is now possible to screen populations for these defects. Despite the vast heterogeneity of these disorders, it has turned out in practice that in each given geographic and ethnic area there is a reproducible pattern of recurrent abnormalities, such that diagnostic accuracy can be achieved using relatively small numbers of probes [1,23]. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

The effectiveness and difficulties of screening is illustrated in a report from Indonesia where issues of education, awareness of the disorder, and stigmatization emerged [24].

Oral iron chelating agents — Availability of inexpensive, orally effective iron chelating agents would dramatically reduce costs and increase the effectiveness of available medical treatment of thalassemia. Deferiprone is in widespread use in the United States, as is the orally active tridentate iron chelator deferasirox (brand names Exjade and Jadenu), which can be given once daily. Long-term benefits of both agents have been reported. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

Financial problems — Transfusion support requires a blood procurement program that has appropriate storage capacity, excellent donor identification, and the capability of screening for blood-borne infections, such as hepatitis and HIV. These screening tests are sophisticated and expensive. The problems of supporting the medical needs of these patients fall primarily on local programs in developed countries.

Community-wide problems — Understanding the molecular and genetic basis of the thalassemias has allowed us to apply this information to communities and entire countries [5]. As examples, the frequency of the hemoglobin Constant Spring (HbCS) gene in Bangkok is 8 percent, the frequency of the HbE trait in the Southeast Asian triangle is 40 to 60 percent, while the frequency of the alpha thalassemia trait in Melanesia and parts of Nepal have reached 70 and 90 percent, respectively [25,26].

Genetic counseling of couples — To be clinically useful, this screening information has to be coupled with an education program informing local physicians and the affected population about the disease, its manifestations, cause, and clinical course. Following this, there must be accessible opportunities for genetic counseling. As an example, if both parents have beta thalassemia trait, they can be told the following about the chances of an affected child:

Child with severe disease (ie, transfusion-dependent thalassemia) – One chance in four

Asymptomatic carrier (beta thalassemia trait) – One chance in two

Unaffected child – One chance in four

Genetic counseling has generally had little or no impact on the choice of spouse, although separating and finding another spouse was a major option in Iran before prenatal testing was generally available and abortion of an affected fetus was permitted by the government [27]. On the other hand, once pregnancy has occurred, given that community educational programs have been effective, the couple will almost invariably seek prenatal diagnosis, which can be achieved before 13 weeks, using chorionic villus biopsy [5]. (See "Prenatal screening and testing for hemoglobinopathy", section on 'Prenatal (fetal) diagnosis'.)

Depending on the ethnic group and the society, the couple then has an opportunity to choose whether to terminate or continue the pregnancy [27]. As an example, in Cyprus, Sardinia, Italy, and Greece [5], when the couple has been informed that the fetus is affected with beta thalassemia major, over 97 percent of the couples terminated the pregnancy (table 1) [28].

A pilot hospital-based screening and education program on the southeastern coast of China has had similar success [29]. Over an 11-year period from 1993 through 2003, 4587 out of 49,221 screened pregnant women were found to be carriers of alpha or beta thalassemia. Ninety-eight percent of the partners of these women agreed to screening, and 281 of the couples were found to be at risk for severe thalassemia. Prenatal diagnosis was performed in 269 (95.7 percent) of the 281 at-risk pregnancies, which identified 69 severely affected fetuses (25.6 percent). All pregnancies with severely affected fetuses were voluntarily terminated.

During this time there were only two affected children born at this large regional hospital, both with homozygous alpha (0) thalassemia. These children were from the 12 couples that refused to accept prenatal diagnosis.

Ethical issues — An important question that has arisen is whether it is ethical to provide prenatal screening services designed to detect fetal abnormalities, such as alpha or beta thalassemia major, without providing increased access to abortion. As an example, Iran has tackled this issue by liberalizing its abortion laws for fetuses with thalassemia [30]. Other major ethical issues include the following [31]:

The techniques for preimplantation genetic diagnosis and therapy have been developed for single gene disorders such as the thalassemias. These techniques might be employed by a couple at risk in order to select an uninvolved embryo for implantation, although the efficacy is limited. (See "Prenatal screening and testing for hemoglobinopathy", section on 'Prenatal (fetal) diagnosis'.)

These techniques might also be employed if there is a severely affected child with thalassemia major who lacks an HLA-matched sibling donor for a curative allogeneic hematopoietic cell transplantation (HCT). Through the use of these single cell genetic methods, the parents' fertilized eggs might be screened to select one that is not thalassemic and is also HLA compatible with the affected child [32,33]. This fertilized egg is then implanted in the mother, and, at the time of delivery, cord blood stem cells are harvested for use in the subsequent allogeneic HCT for the affected child.

Clearly, there are very important ethical and financial issues involved in these two scenarios.

IMMIGRATION PATTERNS AND PROVISION OF HEALTH CARE — In the individual Mediterranean countries such as Greece and Italy, there is a commonality of language, culture, and religion, and there are strong state-supported health care systems. However, with current immigration patterns, people from Southeast Asia are being cared for in countries with different languages, cultural norms [5,6,34], and health care systems. This has led to a number of problems in education occurring at several different, but interrelated, levels.

Physician education — Few physicians in the United Kingdom, Canada, and the United States have experience caring for patients with severe thalassemia. This care requires knowledgeable physicians with the requisite diagnostic facilities, including relevant molecular biologic probes; laboratory and transfusion support; access to magnetic resonance imaging (MRI) methods such as T2* imaging to determine organs of iron overload accurately and knowledge about stunted growth, endocrine disorders, bone disease, facial deformities, delayed puberty, and management of infections, splenomegaly, and viral hepatitis.

Thus, physicians in communities to which people from Southeast Asia have immigrated must be trained in all of the above aspects of care. Furthermore, since patients with severe thalassemia are surviving into their 30s and 40s, one or more other changes must occur [35]:

Physicians who care primarily for adults and are inexperienced in caring for people with thalassemia must be taught to care for these patients.

Pediatricians, the traditional caregivers of the past, will have to continue to take care of such patients well after the onset of puberty.

A formalized and consolidated transition program can be implemented, as occurs with sickle cell disease (see "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care"). In many countries, such a program exists but is not implemented, and people with thalassemia remain in pediatric wards until adulthood and perhaps older adulthood.

Translators and other clinicians — In the short term, ensuring effective communication between the affected individuals and their caregivers, community facilities, and the medical community requires the provision of adequate numbers of language translators and appropriate community role models, such as nurse practitioners and other health care providers who speak the same language as the patient [34].

Community educational programs — The community and its leaders must be educated about these diseases, options for management, and the available facilities. Community leaders, in turn, must ensure that opportunities exist for locally obtaining the necessary genetic counseling, prenatal testing, and appropriate medical care.

The most effective intervention thus far has been population screening to identify ethnic-specific patterns of molecular abnormalities, genetic counseling combined with highly reliable prenatal diagnosis, followed by community and social support that allows the affected couple to choose to act on the information and terminate an affected pregnancy [1,5,6,36-38]. While such molecular diagnostic programs are expensive, they are remarkably cost-effective, as demonstrated in Cyprus, Sardinia, Italy, and Greece [1,5,36].

Examples of effective community action — The experience of three countries has given us a clear description of an optimal support system [6,39,40].

Greece — There are 3500 patients with severe beta thalassemia major in Greece, who consume one-quarter of the country's total blood supply. Iron chelation therapy alone costs 7 million dollars per year. Accordingly, Greece has generated an extensive educational program to produce public awareness. This is coupled with easy access to a program of prenatal diagnosis and screening, along with a very extensive social support program (table 2) [6]. The persistence of these important benefits will depend on the evolving financial status of the country.

Parent groups have been encouraged to the extent that 90 percent of thalassemic patients use the support system and are aware of the issues surrounding this disorder (table 3) [6]. Psychosocial support is also provided as an integral part of this scheme, such that the psychosocial burden has changed significantly (table 4 and table 5) [6]. It would be difficult to envision a more extensive and comprehensive program. As a direct result of this effort, the average age of beta thalassemia major patients in Greece is now 27, and very few new patients with beta thalassemia major are being born (figure 1) [6].

Italy — A very similar program, although not quite so extensive, is provided in Italy.

A study compared the 170 Ferrara patients with 300 patients in the Athens thalassemia program [39]. Surprisingly, the psychosocial adjustment in Ferrara, when formally assessed, was better than that in Athens, where there was considerable hostility and only 30 percent of patients were adherent to chelation therapy. It has been stated that "Illness dominates all aspects of life" in Athens, but not in Ferrara [6,39]. In Ferrara, adjustment was good, even leading to marriage and children, with the social support being provided mainly by the family structure and its religion. One wonders whether the maximal program in Greece has led to unrealistic expectations.

Cyprus — Before 1976, the birth rate for severe thalassemia in Cyprus was 18 to 20 cases per year. The following actions were taken to reduce this serious health problem [40]:

Screening high-risk kindreds for thalassemia was started in 1979

Premarital screening was made compulsory in 1980

Prenatal diagnosis with fetal blood sampling was started in 1984

DNA techniques replaced fetal blood sampling in 1991

Facilities were provided for treatment of existing thalassemic patients

As a result of these actions, the birth rate for severe thalassemia between 1991 and 2001 had dropped to one case every two to three years, and there were no such births during the following five years. Two-thirds of the existing patients with severe thalassemia are now >35 years of age, living and working in the same way as the normal population; more than 38 percent are married with children.

China — The exact number of cases of thalassemia in China is not known, but it is clear that this disease strains health resources in that country. To ease this burden, the Chinese government has embarked on a comprehensive prevention program featuring population screening, prenatal diagnosis, and genetic research funding, with a goal to do as well as the program initiated in Cyprus [41].

Of great importance is the hematopoietic stem cell transplant program carried out in China, with an impressive number of cases and outstanding results in children, showing that transplantation is feasible in many parts of the world [42].

The cost-benefit ratio of an alpha thalassemia prevention program has been conducted in Hong Kong, and has concluded that universal prenatal screening for the alpha and beta thalassemias with the use of DNA testing is cost-effective [43].

Other countries — Cost-benefit analyses of beta thalassemia programs in Quebec, Iran, Israel, and the United Kingdom have generally confirmed the overall benefits of such programs, in that the costs of prevention were lower than the costs of treatment [2,44-48].

COMPONENTS OF A SUCCESSFUL PROGRAM — There is certainly a need to educate physicians about this disease and its management, as well as to have an explicit local, regional, and national policy to cover antenatal and prenatal screening for these hemoglobinopathies [49]. It is, however, critical to inform and empower the affected ethnic groups now living in the developed world. (See "Prenatal screening and testing for hemoglobinopathy", section on 'Prenatal (fetal) diagnosis'.)

The Oakland, California group has found that language translators and nurse practitioners from the affected ethnic groups are very important for the success of these programs. Contact also needs to be made with community leaders to educate, inform, and involve them in community educational programs. Weekly meetings among patients, parents, community leaders, and the medical staff to discuss issues and problems are of paramount importance. Other effective programs would include special family nights, health fairs, and language-specific literature, including information concerning subjects such as genetic counseling, prenatal diagnosis, management of intercurrent illness, sexual development, pregnancy, and osteopenia [9,34,35,50,51].

SUMMARY AND RECOMMENDATIONS

Problem overview – Beta thalassemia occurs in the Mediterranean littoral and all over Southeast Asia (Burma, Thailand, Cambodia, Vietnam, China, Malaysia, Indonesia, and the Philippines). Alpha thalassemia is even more common, occurring with high frequency in Southeast Asia, Africa, and India. A number of issues concerning thalassemia have important public health implications in these countries as well as in the developed world. These include the following (see 'Introduction' above and 'Severe thalassemia in the developed world' above):

By 1970, it was projected that, if thalassemia was not controlled in Cyprus, by the year 2000 the cost of treatment of these children would consume the entire health care budget of Cyprus and require all of the blood that the island could supply.

There are 3500 patients with severe beta thalassemia major in Greece, who consume one-quarter of the country's total blood supply. Iron chelation therapy alone costs 7 million dollars per year.

Before 1980, hemoglobin E (HbE) was not recognized in California. With approximately 10 percent of the California population comprised of Asian Americans, the number of children born with thalassemia is increasing and the number of births in California of children with homozygous HbE disease exceeds the number of births of children with sickle cell disease.

In the individual Mediterranean countries such as Greece and Italy, there is a commonality of language, culture, and religion, and there are strong state-supported health care systems. However, immigration patterns have led to the situation where individuals of Southeast Asian ancestry are receiving care in countries with different languages, cultural norms, and health care systems.

Potential solutions – Solutions to the above problems require action on all of the following levels (see 'Components of a successful program' above and 'Examples of effective community action' above):

Education of health care providers. (See 'Physician education' above and 'Translators and other clinicians' above.)

Effective community educational programs. (See 'Community educational programs' above.)

Effective counseling of couples at risk of having an affected child. (See 'Genetic counseling of couples' above.)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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Topic 7117 Version 23.0

References

1 : Thalassemia in the next millennium. Keynote address.

2 : Theα-thalassemias.

3 : The Prevention of Thalassemia Revisited: A Historical and Ethical Perspective by the Thalassemia International Federation.

4 : Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem.

5 : Global epidemiology of hemoglobin disorders.

6 : The psychosocial impact of chronic illness.

7 : The psychosocial impact of chronic illness.

8 : The psychosocial impact of chronic illness.

9 : Impact of Asian immigration on thalassemia in California.

10 : Clinical manifestations ofα-thalassemia.

11 : The hemoglobin E syndromes.

12 : Screening and counseling for thalassemia.

13 : Patients with thalassemia in the United States.

14 : Changes in the epidemiology of thalassemia in North America: a new minority disease.

15 : Newborn screening in the Asia Pacific region.

16 : Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group.

17 : alpha-Thalassaemia.

18 : Survival and disease complications in thalassemia major.

19 : Pathophysiology of iron overload.

20 : Costs and cost-effectiveness of allogeneic stem cell transplantation in children are predictable.

21 : Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen.

22 : Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.

23 : Development of bead-based suspension array technology for the diagnosis of thalassemia.

24 : Feasibility of preconception screening for thalassaemia in Indonesia: exploring the opinion of Javanese mothers.

25 : High frequencies of alpha-thalassaemia are the result of natural selection by malaria.

26 : Protection against malaria morbidity: near-fixation of the alpha-thalassemia gene in a Nepalese population.

27 : Iranian national thalassaemia screening programme.

28 : Prevention of beta-thalassemia major and Hb Bart's hydrops fetalis syndrome.

29 : Carrier screening for alpha- and beta-thalassemia in pregnancy: the results of an 11-year prospective program in Guangzhou Maternal and Neonatal hospital.

30 : Prenatal diagnosis and abortion for congenital abnormalities: is it ethical to provide one without the other?

31 : Prenatal whole-genome sequencing--is the quest to know a fetus's future ethical?

32 : Development and clinical application of a strategy for preimplantation genetic diagnosis of single gene disorders combined with HLA matching.

33 : Preimplantation HLA testing.

34 : Outreach strategies for Asian Pacific Island (API) communities.

35 : Approaches to working with adult thalassemia patients in pediatric settings.

36 : Thalassemia--a global public health problem.

37 : Screening extended families for genetic hemoglobin disorders in Pakistan.

38 : Effect of consanguinity on screening for thalassemia.

39 : Psychosocial integration of adolescents and young adults with thalassemia major.

40 : Results from the north cyprus thalassemia prevention program.

41 : Genetic disease. China heads off deadly blood disorder.

42 : Long-term results of the NF-08-TM protocol in stem cell transplant for patients with thalassemia major: A multi-center large-sample study.

43 : Cost-effectiveness of prenatal screening for thalassaemia in Hong Kong.

44 : Cost-benefit analysis of a thalassemia disease prevention program.

45 : Evaluation and cost analysis of national health policy of thalassaemia screening in west-azerbaijan province of iran.

46 : Cost-benefit analysis of a national thalassaemia prevention programme in Israel.

47 : Prevention ofβThalassemia in Northern Israel - a Cost-Benefit Analysis.

48 : Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

49 : A national screening policy for sickle cell disease and thalassaemia major for the United Kingdom. Questions are left after two evidence based reports.

50 : The social impact of migration on disease. Cooley's anemia, thalassemia, and new Asian immigrants.

51 : Bone metabolism in thalassemia.