key: cord-0944976-zxqk9q17
authors: Kattamis, Antonis; Forni, Gian Luca; Aydinok, Yesim; Viprakasit, Vip
title: Changing patterns in the epidemiology of β‐thalassemia
date: 2020-09-21
journal: Eur J Haematol
DOI: 10.1111/ejh.13512
sha: 8440a0d5a96316abc50d30329d6b65cbd4b4e497
doc_id: 944976
cord_uid: zxqk9q17

β‐thalassemia major is an inherited hemoglobinopathy that requires lifelong red blood cell transfusions and iron chelation therapy to prevent complications due to iron overload. Traditionally, β‐thalassemia has been more common in certain regions of the world such as the Mediterranean, Middle East, and Southeast Asia. However, the prevalence of β‐thalassemia is increasing in other regions, including Northern Europe and North America, primarily due to migration. This review summarizes the available data on the changing incidence and prevalence of β‐thalassemia as well as factors influencing disease frequency. The data suggest that the epidemiology of β‐thalassemia is changing: Migration has increased the prevalence of the disease in regions traditionally believed to have a low prevalence, while, at the same time, prevention and screening programs in endemic regions have reduced the number of affected individuals. Various approaches to prevention and screening have been used. Region‐specific prevention and treatment programs, customized to align with local healthcare resources and cultural values, have been effective in identifying patients and carriers and providing information and care. Significant challenges remain in universally implementing these programs.

Similarly, an Iranian study showed a decline in affected birth rate from 2.53 per 1000 births in 1995 to 0.82 per 1000 births in 2004. 9 In

Oman, between the years 2005 and 2007, the incidence of β-thalassemia major was 0.08%, with a carrier rate of 2.6%. 10 Approximately 10 years earlier in 1995, the incidence was reported to be 0.4 per 1000 births. 11 In Iraq, the incidence of β-thalassemia decreased from 72.4 per 100 000 live births in 2010 to 34.6 per 100 000 live births in 2015. 12 A comprehensive National Hemoglobinopathy Control Program was implemented by law and came into force on October 24, 2002 , in 33 provinces of Turkey and, by 2008, a 90% reduction in affected newborns in Turkey was achieved. 13 In the United States, β-thalassemia remains a rare disease; in the state of California, the reported incidence is 1 in 55 000 newborns. 14 

Worldwide, approximately 1.5% of people are β-thalassemia carriers. 4 Although the overall combined number of patients with the disease and those who are carriers is known in most countries, significant variations occur even within small geographic regions. 4, 15 The prevalence and carrier rates of β-thalassemia are relatively high in Southeast Asia (Table 1) . [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] For example, the reported prevalence ranges from 1.25% to 1.66% in India 21, 22 but is approximately 2.21% in China. 18, 19 Carrier rates range from 0.5% in Myanmar 16 to 12 .8% in Malaysia. 24 The most recent data on β-thalassemia carrier rates in Southeast Asia are summarized in a review. 20 In the Middle East, the prevalence of β-thalassemia is traditionally high due in part to a high carrier rate and a cultural preference for consanguineous marriages (Table 2) . 11, 12, 15, 16, [27] [28] [29] [30] [31] However, the introduction of prevention programs in many countries in this region has led to a decrease in prevalence over the last decades. 15 In some European countries, the prevalence of β-thalassemia and other major hemoglobinopathies is increasing due to migration, and major hemoglobinopathies are now the most common genetic rare disease in Europe (Table 3) 

Multiple factors contribute to the changing epidemiology of β-thalassemia. These factors include migration, implementation of β-thalassemia prevention programs, and improved survival rates. 15,33

In 2017, the global number of refugees reached an all-time high of 25.4 million, 48 including many people from regions where β-thalassemia is endemic, such as Syria, Afghanistan, and Myanmar.

Several countries have experienced significant increases in the number of refugees that they host such as Germany, Greece, Italy, Turkey, Lebanon, Iran, and Pakistan. 48 Recently, Italy has accepted many refugees who crossed the Mediterranean Sea, demonstrated by the more than 126 000 applications for asylum submitted in 2017. 48 In one study of patients In the United States, the incidence and prevalence of β-thalassemia has increased significantly because of an increase in immigration from Asian countries in the past decades, 52,53 as well as an increased adoption rate of children with β-thalassemia from China and other countries. According to the Cooley's Anemia Foundation, 12% of patients with β-thalassemia in their US patient database were adopted from other countries. 54 In Asia, economic growth in several emerging countries, such as Thailand and Malaysia, has drawn millions of immigrant workers from neighboring countries who lack standardized care for thalassemia-a result likely to lead to an increased thalassemia burden in the near future. 55

Comprehensive prevention programs include public education, genetic counseling, and population screening, accompanied by prenatal diagnostics. Effective public education is the initial step for all prevention programs. An Iranian study showed that 69% of people who are β-thalassemia carriers were insufficiently knowledgeable regarding the prevention of β-thalassemia in their potential offspring, 

and only 13% participated in screening. 56 In many European countries, including France, The Netherlands, Italy, Spain, and the United Kingdom, local and national campaigns are often driven by patient organizations and aim to improve education and awareness for hemoglobinopathies. 32 Such campaigns are most successful if they include the broader community, including educational and religious organizations. 32, 57 Screening programs are being developed in multiple countries and are tailored to local needs and customs. 4 Currently, many screening programs are often unstructured and highly dependent on the knowledge of healthcare professionals and patients. 32 Screening programs generally target possible carriers or at-risk patient populations. 32 Population screening, premarital screening, preimplantation genetic diagnosis, and prenatal diagnosis offer information and choices to at-risk individuals and couples. 44 Factors for efficacy include cultural aspects such as awareness, stigmatization, religious considerations, and whether pregnancy discontinuation (in the event of an affected fetus) is legal and morally accepted in the respective country. 58 While participation in screening programs takes place on a voluntary basis in most countries, some countries have chosen to implement mandatory premarital screening for β-thalassemia (Tables 2   and 3 ). Following a participation rate of only 20% in voluntary premarital counseling, the government of Bahrain decided to make the screening program mandatory in 2004, although the autonomy of the couple regarding testing is fully respected. 16 Other countries with mandatory screening programs include Lebanon, 16 Turkey, 41 and the United Arab Emirates. 27 These programs are well established in many European countries where β-thalassemia has been historically endemic, such as Greece,

Italy, and Cyprus, and in countries that receive a high number of immigrants from endemic countries, such as the United Kingdom and France. 32 In Italy, policies for the prevention of hemoglobinopathies have been in place since the 1970s. 59, 60 Free voluntary carrier screening as well as prenatal and preimplantation genetic diagnostics are available nationwide. 57, 60 Increasing awareness among the general population, leading to acceptance of screening, has been a major success factor of the Italian prevention program. 32, 60 In a report covering 40 years of experience with a screening program in Sardinia, the main causes of affected births (3-5 annually in recent years) were false paternity and decline of prenatal screening and pregnancy termination. 59, 60 In Sicily, an 85% decrease in the incidence of β-thalassemia major and sickle cell anemia (from 1 in 245 live births to 1 in 2000) has been documented following 30 years of preventative measures, which included legislative action, a public awareness campaign, screening and carrier diagnostics, genetic counseling, and prenatal diagnosis. 61 In addition, a universal screening program for hemoglobinopathies is active for couples before and/or after conception, according to Italian law, given that Italy is considered an area endemic for hemoglobinopathies. 61 In Cyprus, a prevention program was introduced in 1973 and has led to a significant decrease in the number of affected babies born. 45 Similarly, the Greek National Prevention Program for thalassemia and other hemoglobinopathies was initiated in 1974 and includes education and prenatal diagnosis. The program led to a significant decrease in the number of affected newborns, from 150 to 200 new cases per year before the screening program, to fewer than 5

cases per year by 2010. 8, 62 Except for an unexplained increase in 2011, the number of affected births has been declining for β-thalassemia major and has remained low for β-thalassemia intermedia. 38 The main causes of affected births were lack of medical care due 72 In Iran, the β-thalassemia prevention program was introduced in 1991, and, by 2001, more than 2.7 million couples had been screened. 73 Utilization of prenatal testing can vary by ethnic group. In the United Kingdom, the utilization rate was more than 90% in couples of Mediterranean origin but only 20% in couples of Asian (mainly Pakistani) origin. 44 In Southeast Asia, Thailand has paved the way for prenatal screening and prenatal diagnosis of thalassemia, as mentioned above; illustrating this, a pilot study of international collaboration between Thailand and Laos primarily focusing on prenatal diagnosis proved to be an effective way to identify thalassemia carriers. 74, 75 Screening of pregnant women and their partners took place in Laos, and laboratory samples were analyzed in the neighboring country of Thailand. 75 However, a recent survey of migrant workers in Thailand, especially those from Myanmar and Cambodia, showed that there is insufficient knowledge about all aspects of thalassemia, including prevention and control, because no national program exists for thalassemia and infrastructure to support screening is lacking. 55 Traditionally, obstacles to the efficacy of prevention programs have been consanguineous marriages, religious beliefs, and low socioeconomic status. Consanguineous marriages are a particularly common tradition in many regions where β-thalassemia is endemic, such as North Africa and the Middle East, thereby increasing the risk of autosomal recessive diseases. 15 In a Turkish observational prospective study of 1988 patients, of whom 94% were diagnosed with β-thalassemia major or intermedia, almost one-half (48%) were born to consanguineous parents. 63 Similarly, an Egyptian study of 44 patients with β-thalassemia reported that 60.6% had consanguineous parents. 28 Another possible limitation of screening programs is the unwillingness of healthcare professionals to offer prenatal diagnostic screenings and pregnancy terminations to their patients. In a Malaysian questionnaire study, 98% of healthcare professionals agreed that they would discuss prenatal diagnostics with their patients, whereas only one-half of them were prepared to discuss termination of pregnancy. 76 The most frequently cited reasons not to discuss termination of pregnancy were the disease not being considered serious enough (54.9%) and abortion not being allowed by their religion (17.6%) or by law (13.7%). 76 Defining the prevalence of the disease in each country is important to properly organize health system resources. Hemoglobinopathies have an important impact on healthcare. 32 Between the years 1997 and 2010, a total of 4506 patients with hemoglobinopathies in a

Greek registry were found to require 18% of the country's total red blood cell supply. 77 β-thalassemia also poses a significant economic burden on healthcare systems. In the United Kingdom, total healthcare expenditure attributable to managing β-thalassemia major over 

Survival rates have significantly improved in countries with adequate health resources where clinicians and patients adhere to guidelines. 32 and liver carcinoma (13.8%) being the most common causes of death. 8 An update of this registry showed that the total number of patients with thalassemia major decreased as age increased, with the majority of patients being middle-aged. 38 In a retrospective cohort study that included 911 patients with β-thalassemia in Iran, the 20-, 40-, and 60-year survival rates were 85%, 63%, and 54%, respectively. 89 Education, marital status, ferritin level, and presence of comorbidities significantly influenced survival rates.

Comparable results were reported by Zamani and colleagues, who reported 10-, 20-and 30-year survival rates of 98.3%, 88.4%, and 80.5%, respectively. 90 In contrast, in Thailand, only 20% of patients with β-thalassemia major reached their fourth decade of life, mainly because they received inadequate blood transfusions and ICT in the past. 91 Therefore, it is unsurprising that the number of surviving patients with β-thalassemia major in the current registry was lower than one would expect based on genetic epidemiology alone ( Figure 1 ). 5, 7, 8, 11, 38, 44, 63, 91, 92 

Most of the data included in this review derives from published registries for hemoglobinopathies in general and β-thalassemia specifically ( Figure 1 ). Registry data provide epidemiological data as well as information on the effectiveness of treatment, screening programs, and public health and education programs using one or more data sources. 11 Importantly, the increasing prevalence in these countries has increased the burden on healthcare systems. As long as migration to these regions continues, for example, due to economic, social, or environmental reasons, the prevalence of β-thalassemia will con- It can be difficult to measure the specific incidence and prevalence of β-thalassemia in countries where β-thalassemia is relatively rare and no screening programs are available. Differences in methodology in data collection and reporting further limit the availability of epidemiologic data. Most studies do not differentiate between the frequency of β-thalassemia major and intermedia, while others include other hemoglobinopathies, such as sickle cell disease or α-thalassemia. Collecting and publishing data for β-thalassemia overall and for its subtypes separately will help provide more insight into the epidemiology of this disease, especially if these data were to be reported by regions within a country where relevant differences between regions exist.

For observational studies, including registries, insufficient reporting of patients as well as missing data in registries may limit the ro- 

All authors have reviewed the manuscript, believe it represents valid work, and approve it for publication. All authors participated in research design, performance of the research, data analysis, and writing of the manuscript.

Data sharing not applicable to this article as no datasets were generated during the current study.

https://orcid.org/0000-0002-5178-0655

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