PUBLIC HEALTH REVIEWS

Global epidemiology of haemoglobin disorders and derived service indicators

Epidémiologie mondiale des troubles de l'hémoglobine et indicateurs de service dérivés

Epidemiología mundial de las hemoglobinopatías e indicadores de los servicios correspondientes

Bernadette Modell¹; Matthew Darlison

WHO Collaborating Centre for Community Control of Hereditary Disorders, UCL Centre for Health Informatics and Multiprofessional Education (CHIME), Archway Campus, Highgate Hill, London N19 5LW, England

ABSTRACT

To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of haemoglobin disorders. We obtained data on demographics and prevalence of gene variants responsible for haemoglobin disorders from online databases, reference resources, and published articles. A global epidemiological database for haemoglobin disorders by country was established, including five practical service indicators to express the needs for care (indicator 1) and prevention (indicators 2–5).
Haemoglobin disorders present a significant health problem in 71% of 229 countries, and these 71% of countries include 89% of all births worldwide. Over 330 000 affected infants are born annually (83% sickle cell disorders, 17% thalassaemias). Haemoglobin disorders account for about 3.4% of deaths in children less than 5 years of age. Globally, around 7% of pregnant women carry b or a zero thalassaemia, or haemoglobin S, C, D Punjab or E, and over 1% of couples are at risk. Carriers and at-risk couples should be informed of their risk and the options for reducing it. Screening for haemoglobin disorders should form part of basic health services in most countries.

RÉSUMÉ

Présentation d'une méthode utilisant des données d'épidémiologie génétique pour évaluer les besoins en matière de services équitables et d'un bon rapport coût/efficacité pour le traitement et la prévention des troubles de l'hémoglobine. Des données démographiques et de prévalence concernant les variants génétiques responsables des troubles de l'hémoglobine ont été réunies à partir de bases de données en ligne, de sources de références et d'articles publiés. Une base de données épidémiologiques mondiale sur les troubles de l'hémoglobine par pays a été mise en place, en même temps que cinq indicateurs de service pratiques, destinés à évaluer les besoins en termes de soins (indicateur 1) et de prévention (indicateurs 2 à 5).
Les pays où les troubles de l'hémoglobine sont un problème de santé important représentent 71 % des 229 pays considérés et totalisent aussi 89 % de la natalité mondiale. Plus de 330 000 nourrissons naissent chaque année avec de tels troubles (83 % avec une drépanocytose, 17 % avec une thalassémie). Les troubles de l'hémoglobine sont responsables d'environ 3,4 % des décès chez les moins de 5 ans. A l'échelle mondiale, 7 % environ des femmes enceintes sont porteuses d'une bêta-thalassémie ou d'une alpha-zéro-thalassémie, ou encore d'une hémoglobine S, C, D-Punjab ou E, et plus de 1 % des couples sont à risque. Les porteurs et les couples à risques doivent être informés des dangers qu'ils encourent et des solutions pour les réduire. Le dépistage des troubles de l'hémoglobine doit faire partie des services sanitaires de base de la plupart des pays.

RESUMEN

Demostrar la validez de un método basado en datos de epidemiología genética para evaluar las necesidades de servicios equitativos y costoeficaces de tratamiento y prevención de las hemoglobinopatías. Se obtuvieron datos demográficos y sobre la prevalencia de las distintas variantes de genes causantes de hemoglobinopatías a partir de bases de datos en línea, de referencias y de artículos publicados. Se creó una base de datos epidemiológica mundial sobre las hemoglobinopatías por países, incluidos cinco indicadores prácticos de servicios para expresar las necesidades de atención (indicador 1) y de prevención
(indicadores 2 a 5).
Las hemoglobinopatías representan un importante problema sanitario en un 71% de los 229 países considerados, y en ese 71% se producen el 89% de todos los nacimientos. Cada año nacen más de 330 000 niños afectados (83% de casos de anemia de células falciformes y 17% de casos de talasemia). Las hemoglobinopatías causan aproximadamente un 3,4% de las defunciones entre los niños menores de 5 años. A nivel mundial, en torno a un 7% de las mujeres embarazadas son portadoras de talasemia b o a cero, o de hemoglobina S, C, D Punjab o E, y mas de un 1% de las parejas corren riesgo. Se debería informar a los portadores y a las parejas en riesgo de ese peligro y de las opciones para mitigarlo. El cribado de las hemoglobinopatías debería formar parte de los servicios básicos de salud en la mayoría de los países.

Introduction

Inherited haemoglobin disorders (sickle-cell disorders and thalassaemias) were originally characteristic of the tropics and subtropics but are now common worldwide due to migration.^1–4 Since they can be controlled cost-effectively by programmes that integrate treatment with carrier detection and genetic counselling, WHO has recommended global development of these services.^5,6 However, service development can be unexpectedly challenging, because it requires inclusion of genetic approaches in health systems.

The diversity and heterogeneous distribution of haemoglobin disorders make it necessary to develop strategies at the country level. To assist policy-makers, we use haemoglobin disorders as an example to show how genetic epidemiological data can be interpreted in terms of administrative boundaries (and/or ethnic group) and practical service indicators. The work was initiated for WHO^7,8 and further developed in the United Kingdom,^9,10 where it is used for local needs-assessment.¹¹ Global data are available at: www.chime.ucl.ac.uk/work-areas/cab/.

Genetic terminology can be impenetrable to non-specialists. In this paper, we use terms proposed for more general use by the Professional Education for Genetic Assessment and Screening (PEGASUS) Genetic Education Programme of the United Kingdom National Screening Committee:¹¹ haemoglobin disorders include sickle-cell disorders and thalassaemias; haemoglobin gene variants are haemoglobinopathies; significant variants are gene variants that can cause a serious disorder; carriers are healthy heterozygotes; people with combinations of gene variants are homozygotes and compound heterozygotes; and a thalassaemia major is haemoglobin Barts hydrops fetalis.

Genetic background

Haemoglobin comprises four globin chains: fetal haemoglobin (Hb F) has two a and two gamma chains (a_2¡2) and adult haemoglobin (Hb A) has two a and two b chains (a₂b₂). Genes in the a-globin and b-globin gene clusters (on chromosomes 16 and 11) control globin-chain production. Due to spontaneous mutation, haemoglobin gene variants are present at low prevalence (carriers 1–1.5/1000) in all sizeable populations.^2,12 They fall into two broad groups – structural variants that change the amino acid sequence and produce an unusual haemoglobin,¹³ and thalassaemias that lower or abolish production of globin chains.¹⁴ Most haemoglobin gene variants are rare and many are harmless, but some are common because carriers are less likely than others to die from falciparum malaria. The most common such variant, a plus (a⁺) thalassaemia, is usually harmless. However, people who inherit combinations of haemoglobins S, C, E, D Punjab, b thalassaemia, or a zero (a⁰) thalassaemia may have a serious haemoglobin disorder. In populations in which malaria is (or was) endemic, 3 to 40% of individuals carry one of these significant variants, and the prevalence of haemoglobin disorders ranges from 0.3 to 25 per 1000 live births.⁸

Carriers are easily detected by routine haematological methods and can be forewarned of their reproductive risk. Carriers of structural variants have 30–50% of the variant haemoglobin in their red cells: thalassaemia carriers have small red blood cells and sometimes mild anaemia,³ and b thalassaemia carriers also have over 3.5% of Hb A₂. The resemblance between thalassaemia and iron deficiency can confuse the diagnosis of either disorder.¹⁵

Requirements for treatment

b thalassaemia major causes profound anaemia that kills untreated affected children before the age of 3 years. However, the life expectancy of patients treated with regular blood transfusion and iron-chelation therapy, or bone-marrow transplantation, is approaching normal.^16,17a thalassaemia major causes hydrops fetalis and perinatal death, often with life-threatening obstetric complications for the mother,³ and prenatal diagnosis usually leads to termination of pregnancy. Some cases have recently been saved by intrauterine transfusion, despite a high risk of severe mental and physical handicap.¹⁸

In sickle-cell disorders, sickled red blood cells block small blood vessels and cause anaemia, functional asplenia, episodes of severe pain, and residual organ damage. Most untreated affected children die from infection in early life,¹⁹ but simple steps including neonatal diagnosis, prophylactic antimalarials and antibiotics, access to hospital treatment when needed, and information and support for families greatly improve quality and length of life.²⁰

Requirements for prevention

A policy of detecting carriers and informing them of their risk, and possibilities for reducing it, usually leads to a fall in births and deaths of affected children. Requirements are the same for thalassaemias and sickle-cell disorders. In most countries, the approach develops in three stages.²¹

First, retrospectively informing parents with affected children of their 25% recurrence risk allows them to limit family size²² and, where average family sizes are typically large, this approach can significantly reduce affected birth prevalence. Second, introduction of prenatal diagnosis for couples with affected children enables them to have a family, but has little further effect on affected birth prevalence.²¹ Access may also be limited by economic, medical, social or legal factors. Third, information and prospective carrier screening is provided for the whole population. Choice of strategy varies with social attitudes, costs and opportunities within the health system. The offer of testing in high school^23,24 or before marriage^25–28 allows a wide range of choices and requires the least number of laboratory tests.^26,28 Screening during pregnancy^29,30 enables fewer options, requires more tests, is ethical only if prenatal diagnosis is freely available, and often identifies risk too late for the option of prenatal diagnosis.³¹ When carrier screening is provided without the option of prenatal diagnosis it usually creates public demand for this service.^26,32 Population screening is not the only useful strategy: family studies can be cost-effective where consanguineous marriage is common³³ or carrier prevalence is low.³⁴

The effects of screening depend on the choices made by informed individuals. Birth prevalence of thalassaemia can fall by over 90%^25–28,35 because most at-risk couples limit their family to two healthy children,^22,25,26 there is very high uptake of prenatal diagnosis, and some carriers avoid risk by selecting a non-carrier partner.^25,26 Available data for sickle-cell disorders shows lower use of prenatal diagnosis^36,37 and improved survival of affected children with neonatal diagnosis.

Methods

Acquisition of data

The necessary data sets are available for most countries. We gathered demographic data: population number, age distribution, crude birth rate and infant mortality from the 2003 United Nations Demographic Yearbook;³⁸ under-5 mortality from the United Nations Children's Fund (UNICEF);³⁹ supplementary information from national statistics on the internet, and the Encyclopaedia Britannica. Livingstone's 1985 database of 1351 epidemiological studies of haemoglobin disorders² provides robust global data on carrier prevalence (and so gene frequencies) for structural variants, but is less informative for thalassaemias. Data for thalassaemias were obtained from research reviews,^3,4 country visits, and the former WHO Working Group on Haemoglobin Disorders.⁷ Data for a⁺ thalassaemias are from Weatherall and Clegg.³ Detailed sources and references are available at: www.chime.ucl.ac.uk/work-areas/cab/. For populations where consanguineous marriage is common, a population coefficient of consanguinity (F) must be included when calculating the prevalence of affected conceptions from gene frequencies.⁴⁰ Values for population F were obtained from Dr Alan Bittles' database⁴¹ and older ethnographic sources.⁴²

Calculation of birth prevalences and service indicators

Prevalences of conceptions with 12 combinations of gene variants were calculated for each country from gene frequencies using the Hardy–Weinberg equation:⁴⁰

(p² + Fpq) + 2(pq – Fpq) + (q² + Fpq) = 1

where p is the gene frequency of variant 1, q is the gene frequency of variant 2, and F is the population coefficient of consanguinity.

The results are aggregated here into conceptions per 1000 of: (1) sickle cell disorders (SS, SC, S/b thalassaemia), (2) b thalassaemias (homozygous b thalassaemia, Hb E/b thalassaemia), (3) a thalassaemias (homozygous a⁰ thalassaemia, a⁰/a⁺ thalassaemia), and (4) harmless combinations (CC, C/b thalassaemia, EE, DD, D/b thalassaemia, etc.).

The following five service indicators were obtained for every country by combining prevalences of carriers and affected births with demographic data.

1. Indicator for patient care (N) is the annual conceptions with a haemoglobin disorder in the absence of prevention. Where treatment is not available, N is a measure of childhood mortality due to haemoglobin disorders. Where treatment is available, N indicates the potential annual increase in patients needing care, and enables cost projections.⁴³ Where prevention is available, N provides a baseline for measuring its effect on patient numbers.

2. Indicator for carrier screening is the annual carrier tests required. With antenatal screening this is the annual number of pregnancies (~ births) in risk groups. With premarital or prepregnancy screening, this is the annual number of young people in risk groups reaching reproductive age.

3. Indicator for carrier information and offer of partner testing is the annual carriers detectable by the chosen strategy.

4. Indicator for expert risk assessment and genetic counselling is the annual pregnancies to carrier couples, or new carrier couples, detectable by the chosen strategy.

5. Indicator for the offer of prenatal diagnosis is the annual pregnancies actually at risk (~ 3N to 4 N).

The indicator for neonatal screening for sickle-cell disorders differs with policy. When there is no adult carrier screening, all newborns in risk groups must be tested (indicator 2). When there is prior carrier screening, only infants born to carrier mothers (indicator 3), or to at-risk couples (indicator 5) may need to be tested.

Country estimates

The calculations use the most detailed country data available. These data range from limited historical surveys to detailed micromapping by geographical area or ethnicity. Estimates for 24 countries (including China and India) were derived by aggregating more detailed data. Estimates for 19 countries where haemoglobin disorders occur primarily as a result of migration were obtained by combining data on residents' ethnicity or country of birth with gene frequencies in countries of origin.¹² All estimates are the most conservative permitted by the data (i.e. give minimum figures). Individual country estimates are available at: www.chime.ucl.ac.uk/work-areas/cab.

Findings

Haemoglobin disorders were originally endemic in 60% of 229 countries, potentially affecting 75% of births, but are now sufficiently common in 71% of countries among 89% of births (either in the whole population or among minorities) to require policy-makers to consider the most appropriate strategy for treatment and prevention. Table 1 shows conservative prevalence estimates by WHO region. At least 5.2% of the world population (and over 7% of pregnant women) carry a significant variant. Haemoglobin S accounts for 40% of carriers but causes over 80% of disorders because of localized very high carrier prevalence: around 85% of sickle-cell disorders, and over 70% of all affected births occur in Africa. In addition, at least 20% of the world population carry a⁺ thalassaemia.

Around 1.1% of couples worldwide are at risk for having children with a haemoglobin disorder and 2.7 per 1000 conceptions are affected. Prevention is making only a small impression: affected birth prevalence is estimated at 2.55 per 1000. Most affected children born in high-income countries survive with a chronic disorder, while most born in low-income countries die before the age of 5 years: haemoglobin disorders contribute the equivalent of 3.4% of mortality in children aged under 5 years worldwide or 6.4% in Africa.

Table 2 presents the five service indicators by WHO region and geographical subregion. It also shows the rapid recent spread of haemoglobin disorders with migration (e.g. affected conceptions are now more common in northern and western than in southern Europe).

Indicator 1. Annually there are over 332 000 affected conceptions or births. About 275 000 have a sickle-cell disorder, and need early diagnosis and prophylaxis. About 56 000 have a major thalassaemia, including at least 30 000 who need regular transfusions to survive and 5500 who die perinatally due to a thalassaemia major.

Indicator 2. Most births, 75%, are in countries where haemoglobin disorders are endemic and 13% occur where they are common because of migration, so in principle, 88% of the 128 million women who become pregnant annually should be offered screening.

Indicator 3. Over 9 million carriers become pregnant annually. The risk that their partner is also a carrier ranges from 0.1–40% (global average 14%). In principle, all need information and the offer of partner testing.

Indicator 4. Annually there are at least 948 000 new carrier couples, and over 1.7 million pregnancies to carrier couples. Around 75% are actually at risk. In principle, all need expert risk assessment and genetic counselling.

Indicator 5. Annually there are 1.33 million at-risk pregnancies. In principle, all need the offer of prenatal diagnosis.

Table 3 shows that about 12% of children born with transfusion-dependent b thalassaemia are actually transfused, and less than 40% of those transfused obtain adequate iron-chelation therapy. About 100 000 patients are currently living with regular transfusions, and at least 3000 die annually in their teens or early 20s from uncontrolled iron overload. No comparable data are available for sickle-cell disorders.

Estimated reach of prevention

Systematic carrier screening with the option of prenatal diagnosis is established in parts of Asia (in parts of China, including Hong Kong Special Administrative Region (SAR), Macao SAR, some southern regions and the province of Taiwan, parts of India, the Islamic Republic of Iran, the Maldives and Singapore), parts of the Caribbean and most of southern Europe (except Albania). In Australia, much of north-west Europe, New Zealand and North America, prenatal diagnosis is available and antenatal carrier screening is standard practice. In the United Kingdom this policy identifies only a minority of at-risk couples in time for a truly informed choice: for timely risk detection, screening must be provided through primary health care.³⁵ The same may apply for many countries where the disorders affect primarily ethnic minorities. The aggregated global data suggest a 16% reduction in births of children with thalassaemia and a 4% reduction in births of children with sickle-cell disorders. The greater part of the estimated reduction is attributed to reduced reproduction by informed at-risk couples, rather than prenatal diagnosis.

Discussion

Global burden of haemoglobin disorders

The yardstick of under-5 mortality can be used to assess the broad effect of haemoglobin disorders on health, because most affected children die in early childhood and most survivors have chronic disease. Table 1 shows that they cause the equivalent of at least 3.4% of deaths in children aged under 5 years. However, this still underestimates their burden because inherited disorders affect families. Worldwide, over 1% of couples are at risk for haemoglobin disorders, most have at least one affected child, and most affected children die in early childhood. Although the west African death rate in children aged under 5 years is 18.4%, the rate is 16.5% for children born to couples not at risk for sickle-cell disorders compared with 40% for children born to couples who are at risk. Clearly, methods to assess the health burden of inherited disorders must include a family perspective.⁴⁴

Thalassaemias

Most children with thalassaemia are born in low-income countries. Worldwide, transfusion is available for a small fraction of those who need it, and most transfused patients will die from iron overload unless an available and potentially inexpensive oral iron chelator is licensed more widely.⁴⁵ The patients' predicament underlines the need for combined treatment and prevention programmes.⁴³ Wherever combined programmes exist survival is steadily improving,^16,17 affected births are falling,^25–28,30 and numbers of patients are stabilizing. The policy is spreading because of its demonstrable cost-effectiveness, and thalassaemia is gradually becoming contained.⁴³

Sickle-cell disorders

In high-income countries that provide neonatal diagnosis and care for patients, most survive well into adult life⁴⁶ and, because there is limited use of prenatal diagnosis,^36,37 numbers of patients are rising steadily. Most affected children born in low-income countries still die undiagnosed, usually from malaria,¹⁹ but things are changing. About 40% of Africa is now urbanised, and improved access to health care is leading to increased survival and rising demand for hospital services.⁴⁷ Community-based services including information, prophylactic antimalarials or antibiotics, and social support greatly improve survival and quality of life and reduce demand for acute hospital services – in short, it is less costly to make organized care available than not.⁴⁷ If average survival reaches only half the African norm, over six million Africans will be living with a sickle cell disorder – clearly, care for these disorders must become part of primary care wherever they are common.

There is a strong case for carrier screening in Africa. Cheap and simple methods for testing adults and newborns exist. Knowledge of risk allows a range of options, including limiting of family size, ensuring that at-risk infants are tested at birth, and requesting prenatal diagnosis. DNA-based early prenatal diagnosis is available at several African centres and is relatively inexpensive when only the sickle variant is sought. However, as few couples can afford even a subsidised fee,³² there is insufficient information on likely uptake if the service were freely available.

Relevance to diagnosis of iron deficiency

WHO recommends the use of haemoglobin concentrations to assess prevalence of iron deficiency in a lower-income setting.⁴⁸ However, the recommended cut-off values for haemoglobin concentrations are derived from populations of northern European origin and can lead to overestimation of iron deficiency where thalassaemias are common.^49,50 The high global prevalence of thalassaemias (Table 3) means that each population should use their own baseline normal ranges in the assessment of iron deficiency.

CONCLUSION:

The data summarized here confirm that screening and genetic counselling for haemoglobin disorders should be an intrinsic part of health care in most countries, as recommended by the WHO.^5,6 The country estimates (available at: www.chime.ucl.ac.uk/work-areas/cab) provide a starting point for local needs assessment, service planning and evaluation. Because haemoglobin disorders are commonly a point of entry for genetic approaches into health systems,^43,44 services should be designed to provide a foundation for more comprehensive community genetics services.²⁶

Acknowledgements

We thank numerous international colleagues for helping to collect the data summarized here. We are grateful to the late Frank Livingstone for his invaluable global database of epidemiological studies.

Funding: Bernadette Modell is a retired Wellcome Principal Research Fellow. Matthew Darlison is partly funded by PEGASUS, the Genetic Education Programme of the United Kingdom National Screening Committee.

Competing interests: None declared.

References

1. Livingstone FB. Abnormal hemoglobins in human populations. Chicago: Aldine; 1967.         

2. Livingstone FB. Frequencies of hemoglobin variants. New York and Oxford: Oxford University Press; 1985.         

3. Weatherall DJ, Clegg JB. Distribution and population genetics of the thalassaemias. 4th ed. Oxford: Blackwell Science; 2001. Chapter 6.         

4. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ 2001;79:704-12. PMID:11545326        

5. Sickle cell anaemia. Agenda item 11.4. In: 59th World Health Assembly, 27 May 2006. WHA 59.20. Available from: http://www.who.int/gb/ebwha/pdf_files/WHA59-REC1/e/WHA59_2006_REC1-en.pdf [p. 26; accessed on 6 February 2008]          .

6. Thalassaemia and other haemoglobinopathies. Agenda item 5.2. In: 59th World Health Assembly, 27 May 2006. EB118.R1. Available from: http://www.who.int/gb/ebwha/pdf_files/EBSS-EB118-2006-REC1/english/Res/res-eb118_2006_rec1-en.pdf [accessed on 6 February 2008]          .

7. Community control of hereditary anaemias: memorandum from a WHO meeting. Bull World Health Organ 1983;61:63-80. PMID:6601544        

8. Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Ann N Y Acad Sci 1998;850:251-69. PMID:9668547 doi:10.1111/j.1749-6632.1998.tb10482.x        

9. Sickle cell and thalassaemia: achieving health gain: guidance for commissioners and providers. London: Health Education Authority; 1998.         

10. Hickman M, Modell B, Greengross P, Chapman C, Layton M, Gill M, et al. Mapping the prevalence of sickle cell and a-thalassaemia in England: recommended rates for local service planning. Br J Haematol 1999; 104:860-7. PMID:10192451 doi:10.1046/j.1365-2141.1999.01275.x        

11. NHS antenatal and newborn screening programmes. Epidemiological data on haemoglobin disorders in England. Professional Education for Genetic Assessment and Screening (PEGASUS). Available from: www.pegasus.nhs.uk/phnpolicy/indicators.htm. Glossary available from: www.pegasus.nhs.uk/glossary.htm [accessed on 6 February 2008]          .

12. Modell B, Darlison M, Birgens H, Cario H, Faustino P, Giordano PC, et al. Epidemiology of Haemoglobin Disorders in Europe: an overview. Scand J Clin Lab Invest 2007;67:39-69. PMID:17365984 doi:10.1080/00365510601046557        

13. Huisman THJ, Carver MFH, Efremov GD. A syllabus of human hemoglobin variants. Augusta, GA: The Sickle Cell Anemia Foundation; 1996. Available from: http://globin.cse.psu.edu [accessed on 6 February 2008]          .

14. Huisman THJ, Carver MFH, Baysal E. A syllabus of thalassemia mutations. Augusta, GA: The Sickle Cell Anemia Foundation; 1997. Available from: http://globin.cse.psu.edu [accessed on 6 February 2008]          .

15. Wonke B, Modell M, Marlow T, Khan M, Modell B. Microcytosis, iron deficiency and thalassaemia in a multi-ethnic community: a pilot study. Scand J Clin Lab Invest 2007;67:87-95. PMID:17365986 doi:10.1080/00365510601046474        

16. Borgna-Pignatti C, Rigolotto S, De Stefano P, Zhao H, Capellini MD, Del Vecchio G, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004; 89:1187-93. PMID:15477202        

17. Telfer P, Coen PG, Christou S, Hadjigavriel M, Kolnakou A, Pangalou E, et al. Survival of medically treated thalassaemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica 2006;91:1187-92. PMID:16956817        

18. Chui DHK, Waye JS. Hydrops fetalis caused by a-thalassaemia: an emerging health care problem. Blood 1998;91:2213-22. PMID:9516118        

19. Fleming AF, Storey J, Molineaux L, Iroko EA, Attai EDE. Abnormal haemoglobins in the Sudan savannah of Nigeria. 1. Prevalence of haemoglobins and relationships between sickle cell trait, malaria, and survival. Ann Trop Med Parasitol 1979;73:161-72. PMID:315211        

20. Serjeant GR. Sickle cell disease. 2nd ed. New York: Oxford University Press; 1992.         

21. Alwan AA. Modell B. Community control of genetic and congenital disorders [EMRO Technical Publications Series 24]. Alexandria: World Health Organization Regional Office for the Eastern Mediterranean; 1997.         

22. Petrou M, Modell B, Shetty S, Khan M, Ward RH. Long-term effects of prospective detection of high genetic risk on couples' reproductive life: data for thalassaemia. Prenat Diagn 2000;20:469-74. PMID:10861711 doi:10.1002/1097-0223(200006)20:6<469::AID-PD857>3.0.CO;2-V        

23. Mitchell JJ, Capua A, Clow C, Scriver CR. Twenty-year outcome analysis of genetic screening programs for Tay-Sachs and beta-thalassemia disease carriers in high schools. Am J Hum Genet 1996;59:793-8. PMID:8808593        

24. Furuumi H, Firdous N, Inoue T, Ohta H, Winichagoon P, Fucharoen S, et al. Molecular basis of beta-thalassemia in the Maldives. Hemoglobin 1998; 22:141-51. PMID:9576331        

25. Angastiniotis MA, Hadjiminas MG. Prevention of thalassaemia in Cyprus. Lancet 1981;1:369-71. PMID:6109998 doi:10.1016/S0140-6736(81)91682-2        

26. Samavat A, Modell B. Iranian national thalassaemia screening programme. BMJ 2004;329:1134-7. PMID:15539666 doi:10.1136/bmj.329.7475.1134        

27. Loukopoulos D. Current status of thalassaemia and the sickle cell syndromes in Greece. Semin Hematol 1996;33:76-86. PMID:8714587        

28. Cao A, Furbetta M, Galanello R, Melis MA, Angius A, Ximenes A, et al. Prevention of homozygous b thalassaemia by carrier screening and prenatal diagnosis in Sardinia. Am J Hum Genet 1981;33:592-605. PMID:7258188        

29. NHS sickle cell and thalassaemia screening programme. Available from: http://www.kcl-phs.org.uk/haemscreening [accessed on 6 February 2008]          .

30. Tongsong T, Wanapirak C, Sirivatanapa P, Sanguansermsri T, Sirichotiyakul S, Piyamongkol W, et al. Prenatal control of severe thalassaemia: Chiang Mai strategy. Prenat Diagn 2000;20:229-34. PMID:10719327 doi:10.1002/(SICI)1097-0223(200003)20:3<229::AID-PD790>3.0.CO;2-3        

31. Qureshi N, Modell B, Modell M. Raising the profile of genetics in primary care. Nat Rev Genet 2004;5:783-90. PMID:15510169 doi:10.1038/nrg1453        

32. Akinyanju OO, Disu RF, Akinde JA, Adewole TA, Otaigbe AI, Emuveyan EE. Initiation of prenatal diagnosis of sickle-cell disorders in Africa. Prenat Diagn 1999;19:299-304. PMID:10327132 doi:10.1002/(SICI)1097-0223(199904)19:4<299::AID-PD503>3.0.CO;2-R        

33. Ahmed S, Saleem M, Modell B, Petrou M. Screening extended families for genetic haemoglobin disorders in Pakistan. N Engl J Med 2002;347:1162-8. PMID:12374877 doi:10.1056/NEJMsa013234        

34. Martins MC, Olim G, Melo J, Magalhaes HA, Rodrigues MO. 1988. Hereditary anaemias in Portugal: epidemiology, public health significance and control. J Med Genet 1993;30:235-9. PMID:8474108        

35. Modell B, Harris R, Lane B, Khan M, Darlison M, Petrou M, et al. Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential enquiry. BMJ 2000;320:337-41. PMID:10657326 doi:10.1136/bmj.320.7231.337        

36. Granda H, Gispert S, Dorticos A, Martin M, Cuadras Y, Calvo M, et al. Cuban programme for prevention of sickle cell disease. Lancet 1991;337:152. PMID:1670797 doi:10.1016/0140-6736(91)90810-C        

37. Modell B, Petrou M, Layton M, Varnavides L, Slater C, Ward RHT, et al. Audit of prenatal diagnosis for haemoglobin disorders in the United Kingdom: the first 20 years. BMJ 1997;315:779-84. PMID:9345170        

38. The United Nations Demographic Yearbook. New York: United Nations; 2003. Available from: http://unstats.un.org/unsd/demographic/products/dyb/ [accessed on 6 February 2008]          .

39. The state of the world's children. United Nations Children's Fund (UNICEF); 2003. Available from: http://www.unicef.org/sowc03/contents/pdf/SOWC03-eng.pdf [accessed on 25 February 2008]          .

40. Bodmer WF, Cavalli Sforza LL. Genetics, evolution, and man. San Francisco: WH Freeman and Co.; 1976.         

41. Bittles AH. Consanguineous marriage: current global incidence and its relevance to demographic research [Research report no 90-186]. Michigan: Population studies center, University of Michigan; 1990. Available from: www.consang.net [accessed on 24 February 2008]          .

42. Murdock GP. Ethnographic atlas. Pittsburgh: University of Pittsburgh Press; 1967.         

43. Alwan A, Modell B. Recommendations for introducing genetics services into developing countries. Nat Rev Genet 2003;4:61-8. PMID:12509754 doi:10.1038/nrg978        

44. Christianson A, Howson M, Modell B. March of dimes global report on birth defects. The hidden toll of dying and disabled children. White Plains, NY: March of Dimes Birth Defects Foundation; 2006.         

45. Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for iron overload. Blood 2003;102:17-24. PMID:12637334 doi:10.1182/blood-2002-06-1867        

46. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44. PMID:7993409 doi:10.1056/NEJM199406093302303        

47. Akinyanju OO, Otaigbe AI, Ibidapo MO. Outcome of holistic care in Nigerian patients with sickle cell anaemia. Clin Lab Haematol 2005;27:195-9. PMID:15938726 doi:10.1111/j.1365-2257.2005.00683.x        

48. Iron deficiency anemia: assessment prevention and control: a guide for programme managers. United Nations Children's Fund, United Nations University & WHO; 2001. Available from: http://whqlibdoc.who.int/hq/2001/WHO_NHD_01.3.pdf [accessed on 24 February 2008]          .

49. Beutler E, West C. Hematologic differences between African- Americans and whites: the roles of iron deficiency and alpha thalassaemia on hemoglobin levels and mean corpuscular volume. Blood 2005;106:740-5. PMID:15790781 doi:10.1182/blood-2005-02-0713        

50. Beutler E, West C. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;107:1747-50. PMID:16189263 doi:10.1182/blood-2005-07-3046        

(Submitted: 11 September 2006 – Revised version received: 14 June 2007 – Accepted: 5 July 2007 – Published online: 4 March 2008)

1 Correspondence to Bernadette Modell (e-mail: b.modell@pcps.ucl.ac.uk).
doi:10.2471/BLT.06.036673