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

Hemoglobinopathies are the most common monogenic disorders in humans; among them, thalassemia constitutes a serious medical and public health problem in high prevalence regions, in a geographical zone ranging from the Mediterranean Basin to China. In addition, migrations over the years have introduced thalassemia to many parts of the world. Although disease-specific programs are in place and accessible to most patients in prosperous countries, this is not the case in developing economies, where more than 75.0% of the patient population is born and lives; this concerns both prevention and treatment programs. In view of the significant improvements in public health and healthcare systems over the past few years, the Thalassemia International Federation has revisited the thalassemia prevention programs, initiatives and policies in some of its member countries, discussing their effectiveness and whether any changes in policy or public attitudes to thalassemia prevention have occurred through the recent years.

Preferences for prenatal diagnosis of sickle-cell disorder: A discrete choice experiment comparing potential service users and health-care providers.

BACKGROUND: Non-invasive prenatal diagnosis (NIPD) for sickle-cell disorder (SCD) is moving closer to implementation and studies considering stakeholder preferences are required to underpin strategies for offering NIPD in clinical practice. OBJECTIVE: Determine service user and provider preferences for key attributes of prenatal diagnostic tests for SCD and examine views on NIPD. METHOD: A questionnaire that includes a discrete choice experiment was used to determine the preferences of service users and providers for prenatal tests that varied across three attributes: accuracy, time of test and risk of miscarriage. RESULTS: Adults who were carriers of SCD or affected with the condition (N=67) were recruited from haemoglobinopathy clinics at two maternity units. Health professionals, predominately midwives, who offer antenatal care (N=62) were recruited from one maternity unit. No miscarriage risk was a key driver of decision making for both service users and providers. Service providers placed greater emphasis on accuracy than service users. Current uptake of invasive tests was 63%, whilst predicted uptake of NIPD was 93.8%. Many service users (55.4%) and providers (52.5%) think pressure to have prenatal testing will increase when NIPD for SCD becomes available. CONCLUSIONS: There are clear differences between service users and health professionals' preferences for prenatal tests for sickle-cell disorder. The safety of NIPD is welcomed by parents and uptake is likely to be high. To promote informed choice, pretest counselling should be balanced and not exclusively focused on test safety. Counselling strategies that are sensitive to feelings of pressure to test will be essential.

The parental perspective of thalassaemia in Bangladesh: lack of knowledge, regret, and barriers.

BACKGROUND: Thalassaemia, a hereditary haemoglobin disorder, is a major public health concern in some parts of the world. Although Bangladesh is in the world's thalassaemia belt, the information on this disease is scarce. Additionally, the awareness of this life threatening, but potentially preventable disease is surprisingly poor. However, mass awareness is pivotal for the development of an effective preventive strategy. In this context, the understanding of parental perspectives is essential to grasp the magnitude of the problem. Therefore, this study aimed to investigate the parental knowledge gaps and perceptions regarding thalassemia, the barriers confronted by the parents for caring for their thalassaemic children and their attitude to prenatal screening and prenatal diagnosis. METHODS: This cross-sectional study was conducted between January 2018 and December 2018 at a dedicated thalassemia hospital located in Dhaka. A structured questionnaire was used for face-to-face interviews with parents of thalassaemic children. Descriptive statistics were used to analyse data. RESULTS: Of 365 respondents, nearly all respondents (97%) had not heard about the term, 'thalassemia' before the disease was diagnosed in their children; all (100%) were unscreened for carrier status prior to marriage. Mean knowledge scores were significantly higher in respondents with higher income and education. Most respondents (~ 91%) had a guilty feeling for not undergoing premarital screening. Only around 36% of them had heard about prenatal diagnosis. Approximately 25% participants would consider prenatal diagnosis in a future pregnancy, while 70% of them were unsure and only ~ 5% would decline prenatal diagnosis. Only 9.3% mothers had prenatal diagnosis in a previous pregnancy. Nearly 80% of the parents faced difficulty for obtaining blood donors regularly and a similar proportion (~ 81%) of them did not receive support from any organized blood clubs. More than 40% of the parents reported they felt socially stigmatized. CONCLUSION: This study suggests poor parental knowledge regarding thalassaemia including prenatal diagnosis and the challenges faced while caring for their children. These findings would be of paramount importance in planning and devising effective prevention and intervention strategies in Bangladesh as well as other countries with similar sociocultural setting.

Lack of knowledge and misperceptions about thalassaemia among college students in Bangladesh: a cross-sectional baseline study.

BACKGROUND: Thalassaemia is a potentially life-threatening yet preventable inherited hemoglobin disorder. Understanding local socio-cultural context and level of public awareness about thalassaemia is pivotal for selecting effective prevention strategies. This study attempted to assess knowledge and perceptions about thalassaemia among college students in Bangladesh. METHODS: A supervised cross-sectional survey was conducted on 1578 college students using a self-administered structured questionnaire. The survey took place from 15 February 2018 to 17 March 2018 in the Jamalpur district in Bangladesh. Besides the attitude-related questions, the study asked a total of 12 knowledge-related questions, which were scored on a scale of 0-12 points. RESULTS: Over two-thirds (67%) of the college students had never heard of thalassaemia. The urban-rural dichotomy was observed among those familiar with the term; (46.4% from urban vs. 25.8% from rural colleges). A similar pattern was observed for knowledge score; 5.07 ± 1.87 for students from the urban colleges compared to 3.69 ± 2.23 for rural colleges. Students from the science background had the highest knowledge score (5.03 ± 1.85), while those from arts and humanities background scored lowest (3.66 ± 2.3). Nearly 40% of the students were not sure or did not want to be a friend of a thalassaemia patient. Whereas 39% either declined or remained hesitant about helping thalassaemia patients by donating blood. However, most of the respondents (88%) showed a positive attitude towards 'premarital' screening to prevent thalassaemia. CONCLUSIONS: This study has identified critical knowledge gaps and societal misperceptions about thalassaemia. A better understanding of these aspects will be pivotal for disseminating thalassaemia related information. As the first study of this kind in Bangladesh, findings from this study has generated baseline data that would contribute to developing effective intervention strategies in Bangladesh and other countries with a comparable socio-cultural setting.

Preimplantation genetic diagnosis.

Couples at risk for having an affected child with homozygous thalassemia or other serious hemoglobin disorder have various options for prevention. The most used in some countries has been prenatal diagnosis with a choice of termination of pregnancy. A more recent addition is preimplantation genetic diagnosis (PGD). In this article, this method is described and reviewed.

Rare single gene disorders: estimating baseline prevalence and outcomes worldwide.

As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public health programmes have focused on common genetic disorders. Rare single gene disorders are an important source of morbidity and premature mortality for affected families. When considered collectively, they account for an important public health burden, which is frequently under-recognised. To document the collective frequency and health burden of rare single gene disorders, it is necessary to aggregate them into large manageable groupings and take account of their family implications, effective interventions and service needs. Here, we present an approach to estimate the burden of these conditions up to 5 years of age in settings without empirical data. This approaches uses population-level demographic data, combined with assumptions based on empirical data from settings with data available, to provide population-level estimates which programmes and policy-makers when planning services can use.

Screening extended families for genetic hemoglobin disorders in Pakistan.

BACKGROUND: We have investigated a strategy for identifying and counseling carriers of recessively inherited disorders in developing countries where consanguineous marriage is common. In such communities, gene variants are trapped within extended families, so that an affected child is a marker of a group at high genetic risk. METHODS: Fifteen large Pakistani families, 10 with a history of a hemoglobin disorder and 5 without any such history (controls), were screened for beta-thalassemia and abnormal hemoglobins. All carriers and married couples consisting of two carriers received counseling, and eight families have been followed for two years. RESULTS: In the control families, no carrier was found among 397 members tested. In the 10 families with an index case, 183 of 591 persons tested (31 percent) were carriers; carriers had a 25 percent risk of being in a marriage at risk for producing an affected child, and 17 of 214 married couples (8 percent) consisted of two carriers. No couple at risk was identified among 350 randomly selected pregnant women and their partners. All carriers reported that they have used the information provided in the testing and counseling process: carriers married to carriers with two or more healthy children have avoided further pregnancy, and most such couples with one or no healthy children have used prenatal diagnosis. Seven of eight new marriages and engagements are known not to be at risk. CONCLUSIONS: Testing of extended families is a feasible way of deploying DNA-based genetic screening in communities in which consanguineous marriage is common.

EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies.

Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. Carrier identification and prenatal diagnosis represent valuable procedures that identify couples at risk for having affected children, so that they can be offered options to have healthy offspring. Molecular diagnosis facilitates prenatal diagnosis and definitive diagnosis of carriers and patients (especially 'atypical' cases who often have complex genotype interactions). However, the haemoglobin disorders are unique among all genetic diseases in that identification of carriers is preferable by haematological (biochemical) tests rather than DNA analysis. These Best Practice guidelines offer an overview of recommended strategies and methods for carrier identification and prenatal diagnosis of haemoglobinopathies, and emphasize the importance of appropriately applying and interpreting haematological tests in supporting the optimum application and evaluation of globin gene DNA analysis.

Sperm DNA damage in potentially fertile homozygous beta-thalassaemia patients with iron overload.

BACKGROUND: To test the hypothesis that human sperm DNA could sustain iron-induced oxidative damage and reduce its fertilizing ability, we studied patients with homozygous beta-thalassaemia major (HbTh) as a model of iron overload. METHODS: Sperm from six thalassaemic patients and five age-matched controls were assessed by the sperm chromatin structure assay (SCSA) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay. Semen parameters, endocrine markers of testicular function, iron profiles and the presence of organ dysfunction were also determined. RESULTS: All patients with HbTh were iron overloaded (median ferritin: 2251 microg/l) and had evidence of spontaneous spermatogenesis. Thalassaemic patients had more sperm DNA damage than the controls (P < 0.01). The sperm DNA damage by SCSA and TUNEL were positively correlated (P < 0.05). Sperm motility and TUNEL results were negatively correlated (P < 0.05), while the age of onset of chelation and sperm DNA damage were positively associated with both SCSA (R(2) = 0.80, P = 0.016) and TUNEL data (R(2) = 0.67, P < 0.044). No other biochemical or clinical data were associated with sperm DNA damage. CONCLUSIONS: The increase in sperm DNA damage and the negative correlation between sperm motility and DNA damage suggest that iron overload in HbTh predisposes sperm to oxidative injury. This finding has important implications in assisted reproductive procedures such as ICSI where there is increased risk of transmitting defective DNA to the offspring.

A different molecular pattern of beta-thalassemia mutations in northeast Brazil.

The main hereditary hemoglobin (Hb) disorders of clinical significance in Brazil are sickle cell disease and beta-thalassemia (thal). The sickle gene was introduced by the slave trade, whereas beta-thal was introduced later, due to a massive immigration (mostly by Italians) between 1870 and 1953, mainly to the southeast region of Brazil. Molecular studies performed in the southeast of the country showed a marked prevalence of the nonsense mutation at codon 39 (C --> T) (47-54%), leading to severe forms of beta0-thal. However, the northeast region of the country has a different demographic history, characterized by the absence of the massive Italian immigration. Owing to this and since the majority of cases of beta-thal in Pernambuco, a state located in the northeast of the country, have mild or intermediate clinical and laboratory features, we would predict a different spectrum of beta-thal mutations in this region. We examined 60 unrelated patients (86 beta-thal chromosomes) under regular clinical follow-up in Pernambuco: 6 were regularly transfused beta-thal major subjects, 20 had beta-thal intermedia, 20 had Hb S/beta-thal and 14 were beta-thal trait individuals. The following mutations were found: IVS-I-6 (T --> C) 62.8%, IVS-I-1 (G -->A) 15.1%, IVS-I-5 (G --> C) 9.3%, IVS-I-110 (G --> A) 8.2%, codon 39 (C --> T) 3.5%, and codon 30 (AGG --> AGC) 1.1%. These data show different patterns of beta-thal mutations in two regions of Brazil, demonstrating a thus far unrevealed heterogeneity of the disease in the country.