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Impact and future of screening for haemoglobin disorders
Current Paediatrics (1998) 8, 55-61 © 1998 Harcourt Brace & Co. Ltd
Serial: Screening
Impact and future of screening for haemoglobin disorders
B. Wonke, B. Modell INTRODUCTION
THE MAJOR HAEMOGLOBIN DISORDERS
Haemoglobin disorders (the thalassaemias and sickle cell disorders) are common and severe, and are increasingly important in the UK. Modern management leads to long-term survival in many cases, but the treatment remains complex, burdensome and expensive. Neonatal screening is recommended for sickle cell disorders, since early diagnosis, regular medical supervision and prophylactic antibiotics greatly reduce the risk of sudden death from infection or splenic sequestration? Haemoglobin disorders can also be prevented by carrier screening, followed by genetic counselling and the option of prenatal diagnosis. The Department of Health has advised Districts to develop a policy for treatment and prevention of these disorders, and recommended universal carrier screening of all antenatal patients in Districts where the proportion of births in risk groups exceeds 14%. 2 Though prevention programmes have led to a fall of over 75% in affected births in several Mediterranean countries the effect in the U K has been far smaller? ,4 Consequently, haemoglobin disorders continue to be an important concern for paediatricians, as the number of children requiring treatment continues to increase. In this article we discuss why this is so, and identify ways in which paediatricians can promote services for haemoglobin disorders.
THALASSAEMIAS - ~ SICKLE CELL DISORDERS
Beta Thalassaemia major Haemoglobin E/beta thalassaemia Alpha zero thalassaemia hydrops fetalis Haemoglobin H disease Sickle cell anaemia (Hb SS) Haemoglobin S/C disease Haemoglobin S/beta Thalassaemia Haemoglobin S/D disease
Thalassaemias are caused by under-production of the (z or 13 chains of adult haemoglobin (aJ32). Homozygous beta thalassaemia causes an intractable anaemia requiring blood transfusion for life, and daily subcutaneous infusion of the iron chelating agent Desferal. 5 Cure by bone marrow transplantation is feasible only for a small minority of patients with a suitable donor? Although management is burdensome, compliant patients achieve a good quality of life including education, work, marriage and family. The prognosis indeed in these patients is 'open-ended'. Alpha zero thalassaemia hydrops fetalis is the commonest genetically inherited disorder among people originating from South East Asia and Southern China. It causes stillbirth (or neonatal death) with serious obstetric risks to the mother. 7 Sickle cell disorders are due to structural changes in the ~ chain of adult haemoglobin. In homozygotes they may cause sudden death in infancy, unpredictable painful crises in children, and chronic organ damage resulting in severe morbidity and early mortality. The disease can be highly disruptive of education, work and social integration.
Beatrix WonkeMD, FRC Path, MRCP, Consultant Haematologist, The Whittington Hospital NHS Trust, Highgate Hill, London N19 5NF, UK. Bernadette Modell, FRCP, FRCOG, Professor of Community Genetics, Department of Primary Care and Population Sciences,Archway Resource Centre, Highgate Hill, London N19 5NF, UK Correspondence and requests for offprints to BW.
55
56
CurrentPaediatrics
EPIDEMIOLOGY AND SERVICE INDICATORS The haemoglobin disorders were originally confined to the tropics and sub-tropics but global migrations are spreading them throughout the world. In the U K , around 7% of the population and 11% of births are in ethnic groups at risk for haemoglobin disorders) Table 1 shows carrier frequencies and the resultant birth rate of affected infants in the main at-risk groups in the UK. These figures have been used together with 1991 census ethnicity data to reach estimates of service needs for haemoglobin disorders by Regional and District Health Authorities? Nationally, the frequency of haemoglobin disorders is approaching that of cystic fibrosis, and in most inner cities it exceeds cystic fibrosis. Based on the epidemiological data, District Health Authorities are using minimum indicators for setting up services for haemoglobin disorders. Indicator for:
• antenatal screening = the annual number of pregnant women in groups at-risk = (approximately) the annual number of births in groups at risk. • antenatal carrier counselling = the annual number of pregnant carriers. • expert antenatal counselling and the offer of prenatal diagnosis = the annual number of at risk pregnancies. • neonatal screening = the annual number of births in 'black' ethnic groups. • counselling parents of affected newborns detected by neonatal screening = the annual number of carrier babies born = the annual number of pregnant carriers in 'black' ethnic groups. • services for affected people = the potential number of affected births/year. In the absence of screening and counselling, 170 to 200 infants with major haemoglobin disorders would be born in the U K annually. The estimated costs of patient care for thalassaemia major is £8150-£10 000
per patient per year, and half of this figure for sickle cell disorders. 9 However, when a thalassaemic birth occurs that the parents would have preferred to avoid, it represents an avoidable commitment of around a quarter of a million pounds. Therefore, it seems reasonable to ensure that parents are allowed an informed choice by carrier screening, even in areas where there are few ethnic minorities. 1°
CARRIER SCREENING Haemoglobin disorders can be detected by conventional blood tests with 99% accuracy. The basic haemoglobinopathy screen is shown in Fig. 1. An expert laboratory performs the blood analysis, interprets the results and provides an accurate assessment of genetic risk for the clinician, general practitioner or obstetrician requesting the investigation. Considerable knowledge is needed for risk assessment in the haemoglobin disorders. Though in most cases the diagnosis of carrier status is clear-cut, intermediate, borderline and difficult cases are common.
PRENATAL DIAGNOSIS Prenatal diagnosis was introduced in 1974, and has been widely available since 1980. Initially it was feasible only by fetal blood sampling at around 18 weeks gestation. In 1982 D N A methods were applied for prenatal diagnosis by chorionic villus sampling from as early as 10 weeks of pregnancy. H The introduction of this much more acceptable, simpler and cheaper approach has greatly increased the applicability of prenatal diagnosis. It has enabled the service to extend to Asia and to Islamic countries (Iran and Pakistan), '2 and has increased the uptake of prenatal diagnosis for sickle cell disorders. Table 2 summarizes the U K experience of the acceptability of prenatal diagnosis to different ethnic groups, and at different stages of gestation. If carriers are identified and counselled
Table 1 Estimated prevalenceof carriers of Hb disorders, affectedbirths and at-risk pregnancies in ethnic minority groups in the UK. (Verified 0). Ethnic Group
AS% %
AC %
White Black Caribbean Black African Black Other Indian Pakistani Bangladeshi
11 22 11 + +
4 3 4
Chinese Other Asian Other Other Cypriot Italian
+ 5 0.5-1 +
+
c~° Thal %
Hb E %
Total carriers %
Affected births /1000
Principal risk At-risk pregnancies /1000
0.1 0.9 1 0.9 4.3 4.5 2.8
+ +
+
16 25 16 4.3 4.5 7.3
0.00025 5.6 15.6 5.6 0.46 1.0 0.826
.001 22.4 62.4 22.4 1.85 4.0 3.3
3 3.0 1 16 4
5
8 3.0 6.0 17.5 4
0.85 0.225 1.04 4.33 0.2
3.4 0.9 4.16 17.32 0.8
~ Thal %
+
+ 1.5
+ + + 4.5
Thal SCD SCD SCD [3Thal I] Thal Hb ElI3 Thal, [3Thal ~0 Thal, [3Thal ~ Thal SCD, [3Thal ~ Thal [3Thal
Impact and future of screening for haemoglobin disorders
Red cell indices (automated)
MCH >27pg
~
57
No thalassaemia
1
M C H <27pg = ? thalassaemia
I-IbA2 esti!ation
H b A 2 >3.5%
r- Beta thalassaemia trait
HbA2 = or <3%
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
?iron deficiency ?alpha thalassaemia
~
Serum ferritin or iron r- and TIBC. I f normal, then D N A analysis
S
.'?normal A2 beta thalassaemia trait
: : i
., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Haemoglobin electrophoresis
No abnormal
,
No abnormal
band
haemoglobin
Abnormal band
Sickle test
Positive
Negative
,
Haemoglobin S Further investigation
Quantitation of abnormal haemoglobin Note: A haemoglobinopathy screen most always include both red cell indices and electrophoresis, regardless of the person's ethnic origin. Fig. 1 The haemoglobinopathy screen.
appropriately in time for the option of first trimester diagnosis, new births of thalassaemic children would fall by over 80%, and new births of children with sickle cell disorders would fall by over 60%. Data on actual utilization of prenatal diagnosis now available shows a 50% fall in births of children with thalassaemia, and a 13% fall in births of children with sickle cell disorders; results far below expectation with an optimal service? By contrast, disease-oriented programmes in the Mediterranean area have led to a fall of over 75% in thalassaemic births in Italy, Greece and Cyprus. In the UK the reduction was, and remains, only around 50%. 4 This smaller effect probably reflects the difficulty of
integrating screening into health care in the absence of an official national policy.
AUDIT OF SCREENING AND PRENATAL DIAGNOSIS FOR HAEMOGLOBIN DISORDERS Prevention of genetic disorders can be audited using registers of patients, and of prenatal diagnoses. 4There is no register of patients with sickle cell disorders, but estimates based on census data, mentioned above, can be used. A U K thalassaemia register exists, and Fig. 2
58
CurrentPaediatrics
Table 2 Rate of request for prenatal diagnosis of haemoglobin disorders in the UK Ethnic group
Uptake before 14 weeks gestation
Thalassaemias Cypriot Indian Pakistani South East Asian Sickle cell disorders African Afi'ican Caribbean
Uptake after 14 weeks gestation
>95% >80% 60% >80%
>90% >60% 20% >80%
80% 70%
40% 30%
shows the year of birth of 937 patients (BM, personal communication). Thalassaemia major first appeared in the U K in the late 1950s, when 10% of the population of Cyprus (17% carrying beta thalassaemia) emigrated to London because of political unrest and difficult economic conditions in the island. As they were followed by migrants from other endemic areas, the annual (potential) number of thalassaemic births increased up to over 50 per year, reflecting increasing numbers of people of reproductive age in risk groups. The rising trend has been reversed since prevention became available, but there are wide ethnic differences in the impact of prevention: there are practically no new affected Cypriot births; and most are now among Asians, particularly British Pakistanis. Table 3 shows the result of a pilot enquiry into the circumstances surrounding births of thalassaemic children in 1980-1989. Most were not the result of
Table 3 Results of a U K confidential enquiry into the circumstances of the birth of 107 children with beta thalassaemia major born between 1980 and 1990 Circumstances Born outside the UK Parents declined prenatal diagnosis Parents decided to continue a known affected pregnancy Prenatal misdiagnosis Parents risk not detected, or not counselled, in time for prenatal diagnosis Total
107
FACILITIES FOR SCREENING AND COUNSELLING
A national infrastructure for haemoglobinopathy screening has gradually developed over the past 10 years. Committed specialists are key figures in the screening programme, and most of the 14 NHS Regions now include one or more consultant
_
35
30
.= 25 e.
(11
20
"6 o
z
14 18 6 4 65
informed parental choice, but rather reflected failure to detect risk, or to provide appropriate counselling/3 By using the U K Register of Prenatal Diagnosis for Haemoglobin Disorders and information on livebirths, the 'utilization' of the service can be calculated. Table 4 shows that utilization of prenatal diagnosis for thalassaemia remains at 50% since 1984, and it has risen slightly from 7% to 13% for sickle cell disorders?
UK ([3) THALASSAEMIA REGISTER Year of birth of 937 registered patients 40
Number
15
10
10 30 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 Year
Fig. 2 Year of birth of 937 patients known to the U K thalassaemia register. The chart includes living and deceased patients.
Impact and future of screening for haemoglobin disorders haematologists with a specialist interest in haemoglobin disorders, usually in a conurbation with a high proportion of ethnic minorities. Many specialists have managed to establish a community-based Sickle Cell and Thalassaemia Centre staffed by trained counsellors, and there is now a network of 32 such centres. 14 A national multidisciplinary group with a primary focus on standards of care (the UK Forum on Haemoglobin Disorders) brings together these specialists and counsellors, and other interested parties, creating a national infrastructure for research and audit.
GENETIC RISKS FOR CARRIERS
The high level of genetic risk associated with carrier status is not generally appreciated. Carriers who choose a partner in their own ethnic group have a 3-25% risk of forming an at-risk couple, depending on the carrier frequency in the group. When a carrier child is detected, the parents should be offered carrier screening and genetic counselling. Since 50% of the first degree relatives of a carrier are also carriers, advising carriers to inform their relatives, and encourage them to seek testing when appropriate, can produce a rich haul of positive results. 15 The risks for British Pakistani carriers call for particular attention. Many British Pakistanis marry a relative, and 55% marry a first cousin? 6 Under these circumstances there is a 17% chance that the couple is at risk, population risk of 4% plus a 12.5% risk due to the blood relationship, raising the risk to the same level as the risk for Cypriots.
APPROPRIATE GENETIC COUNSELLING FOR ETHNIC MINORITY GROUPS
A report of the Royal College of Physicians (RCP) ~7 has noted that 'a serious effort should be made to develop an appropriate approach to genetic counselling for all ethnic minorities. For effective counselling, the woman must understand what is said
Table 4
Utilization of prenatal diagnosis for haemoglobin disorders by ethnic group, 1985-94
5-year period 1985-89 Estimated at-risk pregnancies Prenatal diagnoses % utilization of PND
1990-94 Estimated at-risk pregnancies Prenatal diagnoses % utilization of PND
59
and must be able to ask questions.' Many British Pakistanis and Bangladeshis need counselling in their own language and also need time to get used to the many new concepts involved. The RCP report noted that 'British Pakistanis and Bangladeshis should be counselled by a female, ideally a Muslim, in the appropriate language and at home if necessary.'
THE PROCESS OF ANTENATAL SCREENING An audit of the process of antenatal screening for sickle cell disorders, summarized in Fig. 3, casts considerable light on the reasons for the present low service utilization. The obstetric notes were examined of all 31 couples eventually known to be at risk for having children with sickle cell disorders in 1 year (1994) at the Whittington Hospital in North London. 18There were five prenatal diagnoses. Ten of the women had an affected pregnancy, and there were nine live births and one termination. This contrasts with an expected uptake of prenatal diagnosis of over 50%, with appropriate counselling?9 The fact that identification of risk in the first pregnancy did not lead in subsequent pregnancies to fasttrack referral for expert counselling and the offer of prenatal diagnosis, made the process spectacularly inefficient and ineffective. We concluded that other groups of health workers, such as primary care workers and paediatricians, must become much more involved in genetic screening if the service was to be delivered effectively. Ideally paediatricians could help in ensuring appropriate screening and counselling by: • Being aware of the significance of microcytosis, and following it up to obtain a definitive diagnosis of thalassaemia. • When a child is found to carry sickle cell or another abnormal haemoglobin, ensuring that the parents and the GP are informed. • Ensuring that the parents of all children found to carry a haemoglobin disorder are told of the family implications, and offered carrier testing themselves.
AVAILABILITY OF CLEAR AND SIMPLE INFORMATION MATERIALS IS A PRIORITY
At risk for sickle cell disorders
At risk for thalassaemias
All haemoglobin disorders
3163
855
4018
229
475
704
7
56
18
3565
780
4355
457
425
882
13
54
20
The information presented here shows that the health system can be a barrier, rather than mediating genetic information to the public. An adequate infrastructure for genetic screening and counselling is lacking in many areas, and there is a shortage of information materials to help health professionals in informing carriers. People who are found to have a genetic risk need exactly the information that is relevant to them, at that particular time. Thus all the following are needed, and exist, for the haemoglobin disorders.
60
Current Paediatrics Primiparae: GP
Counselling
Booking
25 I
25
25[
__.1
I
20 ]
20
ll,,llll IIIIII ttttnntt
~= 15
'i
o[ ,!11111!I 1
3
5
7
9
11
1
3
5
7
9
1
11
3
5
7
9
I1
Booking
Multiparae: GP
Counselling 25
20
== 2O
o
'i 10 5 D
~
................... 3
5
7
9
11
13
15
17
19
1
3
5
7
9
11
13
15
17
lg
=~11
1
3
5
7
9
11
13 15 17 19
Fig. 3 Gestation at three critical steps in antenatal screening for haemoglobin disorders (first visit to the GP, booking for antenatal care, and counselling) in 31 women at risk for having children with a sickle cell disorder. Those having prenatal diagnosis are shown in black. Most at-risk couples are identified and counselled in their first pregnancy. Forprimiparae, mean interval from seeing the GP to counselling was 7~ weeks and mean gestation at counselling 19 weeks: none requested prenatal diagnosis. (Three did not attend for counselling, including two whose risk was identified only when an affected child was detected by neonatal screening. The risk of an affected child being one in four, around six further couples may have been 'missed' because a carrier mother did not attend for counselling, or her partner was not tested.) The majority of multiparous at-risk women are aware of risk. Most attended their GP early and two were referred for prenatal diagnosis at this stage. The average interval to counselling for the rest was 6 weeks, when three more just achieved a first trimester diagnosis. Four did not attend for counselling, including the two referred by their GP for prenatal diagnosis. In all, one of 10 affected pregnancies was detected prenatally and terminated.
• General information for the public and for pregnant women. • Posters and leaflets to encourage carrier testing. • Diagnosis-specific information for the carriers identified. • Information for couples where both partners have been tested.* • Complete information for at-risk couples. • Information for patients and families about each disorder and its treatment. • Guidelines for doctors on treatment and prevention. • Guidelines for service planners. In fact, all the above have existed for haemoglobin disorders for years, but only the last three have been published. The remainder, though needed in large numbers, have not been printed and counsellors up and down the country have created their own leaflets. Even so, problems of dissemination mean that many patients do not receive them. New approaches based on information technology, and close collaboration between paediatricians and haematologists, are essential to ensure that families and patients are fully informed.
CONCLUSION Every year in the Whittington hospital, and in other London hospitals, seven to ten new patients with sickle cell disorders are diagnosed annually. This represents an increasingly difficult burden for patients, their families and the health service. If the prevention programme is to improve, paediatricians, obstetricians, haematologists, haemoglobinopathy counsellors, and general practitioners need to be aware of the importance of these disorders, and contribute to provision of appropriate screening and information for families. In the out-patient setting, as paediatricians see children with their parents, there is an important opportunity to inform and investigate families in relevant ethnic groups, even when a consultation is unrelated to issues of haemoglobin disorders. This is particularly important when a blood test incidentally suggests a thalassaemia or sickle cell trait. In the inpatient setting, when investigating a child in a relevant ethnic group, a haemoglobinopathy screen should become routine. REFERENCES
*There are many types of haemoglobin disorders and every combination can occur. Specific information is needed for each carrier combination, so 70 different leaflets are required.
1. Serjeant G R. Sickle Cell Disease, 2nd edn. Oxford: Oxford University Press, 1992. 2. Department of Health. Report of a Working Party of the Standing Medical Advisory Committee on Sickle Cell,
Impact and future of screening for haemoglobin disorders 61
3. 4.
5.
6.
7.
8. 9.
10.
Thalassaemia and other Haemoglobinopathies. London: HMSO, 1993. Cao A Rosatelli M C. Screening and prenatal diagnosis of the haemoglobinopathies. Bailli6re's Clinical Haematology 6. 1993: 263-286. Modell B, Petrou M, Layton M, Yarnavides L, Slater C, Ward R H T, Rodeck C, Nicolaides K, Gibbons S, Old J. Audit of prenatal diagnosis for haemoglobin disorders in the United Kingdom: the first 20 years. In press: British Medical Journal 1997; 315: 779-784. Cao A, Gabutti V, Galanello R, Masera G, Modell B, Di Palma A, Piga A, Vullo C, Wonke B. Management protocol for the treatment of thalassemia patients 1997. Obtainable from the Thalassemia International Federation, PO Box 8807, Nicosia, Cyprus. Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, Pokiti R Durazzi S M T, Muretto P, Albertini F. 1990. Bone marrow transplantation in patients with thalassaemia. The New England Journal of Medicine 1977; 322: 417421. Petrou M, Brugiatetli M, Old J, Ward R H T, Kwai Peng Wong, Modell B. Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extractioI1 for alpha thalassaemia trait. British Journal of Obstetrics and Gynaecology 1992; 99: 985-989. Health Education Authority. Sickle cell and thalassaemia: achieving health gain - guidance for commissioners and providers. In press: Guidelines for control of haemoglobin disorders. Unpublished document of the WHO. WHO/HDP/HB/GL/94.1 Obtainable free of charge from the Hereditary Diseases Programme, WHO, Geneva, Switzerland, 1994. Modell B, Anionwu A. Guidelines for screening for haemoglobin disorders: service specifications for low- and high-prevalence district health authorities. In: Ethnicity and
11.
I2. 13.
14.
15.
16. 17.
18. 19.
Health: Reviews of Literature and Guidance for Purchasers in the Areas of Cardiovascular Disease, Mental Health and Haemoglobinopathies. NHS Centre for Reviews and Dissemination/Social Policy Research Unit, CRD Report 5, ISBN No 1 900640 00 7, 1996. Old J M, Ward R H T, Petrou M, Karagozlu F, ModelI B, Weatherall DJ. First-trimester fetal diagnosis for the haemoglobinopathies: three cases. Lancet 1982; 2: 1413-1416. Petrou M, Modell B. Prenatal screening for haemoglobin disorders. Prenatal Diagnosis 1995; 15: 1275-1295. Modell B. EC Concerted action on developing patient registers as a tool for improving service delivery for haemoglobin disorders. In Health Services Research. Eds G N Fracchia, M Theophilaton. Amsterdam: IOS Press, 1993. Anionwu E N. Ethnic origin of sickle and thalassaemia counsellors; does it matter? In: Research in Cultural Differences in Health. Eds D Kelleher, S Hillier. Routledge, London & New York. 1996; 8: 160-189. Monzouras M, Camba L, Ioannou P, Modell B, Constantinides P, Gale R. Thalassaemia as a model of recessive genetic disease in the community. The Lancet 1980; 2: 574-578. Darr A, Modell B. The frequency of consanguineous marriage among British Pakistanis. Journal of Medical Genetics 1988; 25: 186-190. Prenatal diagnosis and genetic screening; community and service implications. A report of the Royal College of Physicians. The Royal College of Physicians of London, London, 1989. Neuenschwander H, Modell B. The process of antenatal sickle cell screening at a North London Hospital. Submitted for publication British Medical Journal 1997; 315: 784-785, Petrou M, Brugiatelli M, Ward R H T, Modell B. Factors affecting the uptake of prenatal diagnosis for sickle cell disease. Journal of Medical Genetics 1992; 29: 820-823.
Serial: Screening
Impact and future of screening for haemoglobin disorders
B. Wonke, B. Modell INTRODUCTION
THE MAJOR HAEMOGLOBIN DISORDERS
Haemoglobin disorders (the thalassaemias and sickle cell disorders) are common and severe, and are increasingly important in the UK. Modern management leads to long-term survival in many cases, but the treatment remains complex, burdensome and expensive. Neonatal screening is recommended for sickle cell disorders, since early diagnosis, regular medical supervision and prophylactic antibiotics greatly reduce the risk of sudden death from infection or splenic sequestration? Haemoglobin disorders can also be prevented by carrier screening, followed by genetic counselling and the option of prenatal diagnosis. The Department of Health has advised Districts to develop a policy for treatment and prevention of these disorders, and recommended universal carrier screening of all antenatal patients in Districts where the proportion of births in risk groups exceeds 14%. 2 Though prevention programmes have led to a fall of over 75% in affected births in several Mediterranean countries the effect in the U K has been far smaller? ,4 Consequently, haemoglobin disorders continue to be an important concern for paediatricians, as the number of children requiring treatment continues to increase. In this article we discuss why this is so, and identify ways in which paediatricians can promote services for haemoglobin disorders.
THALASSAEMIAS - ~ SICKLE CELL DISORDERS
Beta Thalassaemia major Haemoglobin E/beta thalassaemia Alpha zero thalassaemia hydrops fetalis Haemoglobin H disease Sickle cell anaemia (Hb SS) Haemoglobin S/C disease Haemoglobin S/beta Thalassaemia Haemoglobin S/D disease
Thalassaemias are caused by under-production of the (z or 13 chains of adult haemoglobin (aJ32). Homozygous beta thalassaemia causes an intractable anaemia requiring blood transfusion for life, and daily subcutaneous infusion of the iron chelating agent Desferal. 5 Cure by bone marrow transplantation is feasible only for a small minority of patients with a suitable donor? Although management is burdensome, compliant patients achieve a good quality of life including education, work, marriage and family. The prognosis indeed in these patients is 'open-ended'. Alpha zero thalassaemia hydrops fetalis is the commonest genetically inherited disorder among people originating from South East Asia and Southern China. It causes stillbirth (or neonatal death) with serious obstetric risks to the mother. 7 Sickle cell disorders are due to structural changes in the ~ chain of adult haemoglobin. In homozygotes they may cause sudden death in infancy, unpredictable painful crises in children, and chronic organ damage resulting in severe morbidity and early mortality. The disease can be highly disruptive of education, work and social integration.
Beatrix WonkeMD, FRC Path, MRCP, Consultant Haematologist, The Whittington Hospital NHS Trust, Highgate Hill, London N19 5NF, UK. Bernadette Modell, FRCP, FRCOG, Professor of Community Genetics, Department of Primary Care and Population Sciences,Archway Resource Centre, Highgate Hill, London N19 5NF, UK Correspondence and requests for offprints to BW.
55
56
CurrentPaediatrics
EPIDEMIOLOGY AND SERVICE INDICATORS The haemoglobin disorders were originally confined to the tropics and sub-tropics but global migrations are spreading them throughout the world. In the U K , around 7% of the population and 11% of births are in ethnic groups at risk for haemoglobin disorders) Table 1 shows carrier frequencies and the resultant birth rate of affected infants in the main at-risk groups in the UK. These figures have been used together with 1991 census ethnicity data to reach estimates of service needs for haemoglobin disorders by Regional and District Health Authorities? Nationally, the frequency of haemoglobin disorders is approaching that of cystic fibrosis, and in most inner cities it exceeds cystic fibrosis. Based on the epidemiological data, District Health Authorities are using minimum indicators for setting up services for haemoglobin disorders. Indicator for:
• antenatal screening = the annual number of pregnant women in groups at-risk = (approximately) the annual number of births in groups at risk. • antenatal carrier counselling = the annual number of pregnant carriers. • expert antenatal counselling and the offer of prenatal diagnosis = the annual number of at risk pregnancies. • neonatal screening = the annual number of births in 'black' ethnic groups. • counselling parents of affected newborns detected by neonatal screening = the annual number of carrier babies born = the annual number of pregnant carriers in 'black' ethnic groups. • services for affected people = the potential number of affected births/year. In the absence of screening and counselling, 170 to 200 infants with major haemoglobin disorders would be born in the U K annually. The estimated costs of patient care for thalassaemia major is £8150-£10 000
per patient per year, and half of this figure for sickle cell disorders. 9 However, when a thalassaemic birth occurs that the parents would have preferred to avoid, it represents an avoidable commitment of around a quarter of a million pounds. Therefore, it seems reasonable to ensure that parents are allowed an informed choice by carrier screening, even in areas where there are few ethnic minorities. 1°
CARRIER SCREENING Haemoglobin disorders can be detected by conventional blood tests with 99% accuracy. The basic haemoglobinopathy screen is shown in Fig. 1. An expert laboratory performs the blood analysis, interprets the results and provides an accurate assessment of genetic risk for the clinician, general practitioner or obstetrician requesting the investigation. Considerable knowledge is needed for risk assessment in the haemoglobin disorders. Though in most cases the diagnosis of carrier status is clear-cut, intermediate, borderline and difficult cases are common.
PRENATAL DIAGNOSIS Prenatal diagnosis was introduced in 1974, and has been widely available since 1980. Initially it was feasible only by fetal blood sampling at around 18 weeks gestation. In 1982 D N A methods were applied for prenatal diagnosis by chorionic villus sampling from as early as 10 weeks of pregnancy. H The introduction of this much more acceptable, simpler and cheaper approach has greatly increased the applicability of prenatal diagnosis. It has enabled the service to extend to Asia and to Islamic countries (Iran and Pakistan), '2 and has increased the uptake of prenatal diagnosis for sickle cell disorders. Table 2 summarizes the U K experience of the acceptability of prenatal diagnosis to different ethnic groups, and at different stages of gestation. If carriers are identified and counselled
Table 1 Estimated prevalenceof carriers of Hb disorders, affectedbirths and at-risk pregnancies in ethnic minority groups in the UK. (Verified 0). Ethnic Group
AS% %
AC %
White Black Caribbean Black African Black Other Indian Pakistani Bangladeshi
11 22 11 + +
4 3 4
Chinese Other Asian Other Other Cypriot Italian
+ 5 0.5-1 +
+
c~° Thal %
Hb E %
Total carriers %
Affected births /1000
Principal risk At-risk pregnancies /1000
0.1 0.9 1 0.9 4.3 4.5 2.8
+ +
+
16 25 16 4.3 4.5 7.3
0.00025 5.6 15.6 5.6 0.46 1.0 0.826
.001 22.4 62.4 22.4 1.85 4.0 3.3
3 3.0 1 16 4
5
8 3.0 6.0 17.5 4
0.85 0.225 1.04 4.33 0.2
3.4 0.9 4.16 17.32 0.8
~ Thal %
+
+ 1.5
+ + + 4.5
Thal SCD SCD SCD [3Thal I] Thal Hb ElI3 Thal, [3Thal ~0 Thal, [3Thal ~ Thal SCD, [3Thal ~ Thal [3Thal
Impact and future of screening for haemoglobin disorders
Red cell indices (automated)
MCH >27pg
~
57
No thalassaemia
1
M C H <27pg = ? thalassaemia
I-IbA2 esti!ation
H b A 2 >3.5%
r- Beta thalassaemia trait
HbA2 = or <3%
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
?iron deficiency ?alpha thalassaemia
~
Serum ferritin or iron r- and TIBC. I f normal, then D N A analysis
S
.'?normal A2 beta thalassaemia trait
: : i
., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Haemoglobin electrophoresis
No abnormal
,
No abnormal
band
haemoglobin
Abnormal band
Sickle test
Positive
Negative
,
Haemoglobin S Further investigation
Quantitation of abnormal haemoglobin Note: A haemoglobinopathy screen most always include both red cell indices and electrophoresis, regardless of the person's ethnic origin. Fig. 1 The haemoglobinopathy screen.
appropriately in time for the option of first trimester diagnosis, new births of thalassaemic children would fall by over 80%, and new births of children with sickle cell disorders would fall by over 60%. Data on actual utilization of prenatal diagnosis now available shows a 50% fall in births of children with thalassaemia, and a 13% fall in births of children with sickle cell disorders; results far below expectation with an optimal service? By contrast, disease-oriented programmes in the Mediterranean area have led to a fall of over 75% in thalassaemic births in Italy, Greece and Cyprus. In the UK the reduction was, and remains, only around 50%. 4 This smaller effect probably reflects the difficulty of
integrating screening into health care in the absence of an official national policy.
AUDIT OF SCREENING AND PRENATAL DIAGNOSIS FOR HAEMOGLOBIN DISORDERS Prevention of genetic disorders can be audited using registers of patients, and of prenatal diagnoses. 4There is no register of patients with sickle cell disorders, but estimates based on census data, mentioned above, can be used. A U K thalassaemia register exists, and Fig. 2
58
CurrentPaediatrics
Table 2 Rate of request for prenatal diagnosis of haemoglobin disorders in the UK Ethnic group
Uptake before 14 weeks gestation
Thalassaemias Cypriot Indian Pakistani South East Asian Sickle cell disorders African Afi'ican Caribbean
Uptake after 14 weeks gestation
>95% >80% 60% >80%
>90% >60% 20% >80%
80% 70%
40% 30%
shows the year of birth of 937 patients (BM, personal communication). Thalassaemia major first appeared in the U K in the late 1950s, when 10% of the population of Cyprus (17% carrying beta thalassaemia) emigrated to London because of political unrest and difficult economic conditions in the island. As they were followed by migrants from other endemic areas, the annual (potential) number of thalassaemic births increased up to over 50 per year, reflecting increasing numbers of people of reproductive age in risk groups. The rising trend has been reversed since prevention became available, but there are wide ethnic differences in the impact of prevention: there are practically no new affected Cypriot births; and most are now among Asians, particularly British Pakistanis. Table 3 shows the result of a pilot enquiry into the circumstances surrounding births of thalassaemic children in 1980-1989. Most were not the result of
Table 3 Results of a U K confidential enquiry into the circumstances of the birth of 107 children with beta thalassaemia major born between 1980 and 1990 Circumstances Born outside the UK Parents declined prenatal diagnosis Parents decided to continue a known affected pregnancy Prenatal misdiagnosis Parents risk not detected, or not counselled, in time for prenatal diagnosis Total
107
FACILITIES FOR SCREENING AND COUNSELLING
A national infrastructure for haemoglobinopathy screening has gradually developed over the past 10 years. Committed specialists are key figures in the screening programme, and most of the 14 NHS Regions now include one or more consultant
_
35
30
.= 25 e.
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20
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z
14 18 6 4 65
informed parental choice, but rather reflected failure to detect risk, or to provide appropriate counselling/3 By using the U K Register of Prenatal Diagnosis for Haemoglobin Disorders and information on livebirths, the 'utilization' of the service can be calculated. Table 4 shows that utilization of prenatal diagnosis for thalassaemia remains at 50% since 1984, and it has risen slightly from 7% to 13% for sickle cell disorders?
UK ([3) THALASSAEMIA REGISTER Year of birth of 937 registered patients 40
Number
15
10
10 30 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 Year
Fig. 2 Year of birth of 937 patients known to the U K thalassaemia register. The chart includes living and deceased patients.
Impact and future of screening for haemoglobin disorders haematologists with a specialist interest in haemoglobin disorders, usually in a conurbation with a high proportion of ethnic minorities. Many specialists have managed to establish a community-based Sickle Cell and Thalassaemia Centre staffed by trained counsellors, and there is now a network of 32 such centres. 14 A national multidisciplinary group with a primary focus on standards of care (the UK Forum on Haemoglobin Disorders) brings together these specialists and counsellors, and other interested parties, creating a national infrastructure for research and audit.
GENETIC RISKS FOR CARRIERS
The high level of genetic risk associated with carrier status is not generally appreciated. Carriers who choose a partner in their own ethnic group have a 3-25% risk of forming an at-risk couple, depending on the carrier frequency in the group. When a carrier child is detected, the parents should be offered carrier screening and genetic counselling. Since 50% of the first degree relatives of a carrier are also carriers, advising carriers to inform their relatives, and encourage them to seek testing when appropriate, can produce a rich haul of positive results. 15 The risks for British Pakistani carriers call for particular attention. Many British Pakistanis marry a relative, and 55% marry a first cousin? 6 Under these circumstances there is a 17% chance that the couple is at risk, population risk of 4% plus a 12.5% risk due to the blood relationship, raising the risk to the same level as the risk for Cypriots.
APPROPRIATE GENETIC COUNSELLING FOR ETHNIC MINORITY GROUPS
A report of the Royal College of Physicians (RCP) ~7 has noted that 'a serious effort should be made to develop an appropriate approach to genetic counselling for all ethnic minorities. For effective counselling, the woman must understand what is said
Table 4
Utilization of prenatal diagnosis for haemoglobin disorders by ethnic group, 1985-94
5-year period 1985-89 Estimated at-risk pregnancies Prenatal diagnoses % utilization of PND
1990-94 Estimated at-risk pregnancies Prenatal diagnoses % utilization of PND
59
and must be able to ask questions.' Many British Pakistanis and Bangladeshis need counselling in their own language and also need time to get used to the many new concepts involved. The RCP report noted that 'British Pakistanis and Bangladeshis should be counselled by a female, ideally a Muslim, in the appropriate language and at home if necessary.'
THE PROCESS OF ANTENATAL SCREENING An audit of the process of antenatal screening for sickle cell disorders, summarized in Fig. 3, casts considerable light on the reasons for the present low service utilization. The obstetric notes were examined of all 31 couples eventually known to be at risk for having children with sickle cell disorders in 1 year (1994) at the Whittington Hospital in North London. 18There were five prenatal diagnoses. Ten of the women had an affected pregnancy, and there were nine live births and one termination. This contrasts with an expected uptake of prenatal diagnosis of over 50%, with appropriate counselling?9 The fact that identification of risk in the first pregnancy did not lead in subsequent pregnancies to fasttrack referral for expert counselling and the offer of prenatal diagnosis, made the process spectacularly inefficient and ineffective. We concluded that other groups of health workers, such as primary care workers and paediatricians, must become much more involved in genetic screening if the service was to be delivered effectively. Ideally paediatricians could help in ensuring appropriate screening and counselling by: • Being aware of the significance of microcytosis, and following it up to obtain a definitive diagnosis of thalassaemia. • When a child is found to carry sickle cell or another abnormal haemoglobin, ensuring that the parents and the GP are informed. • Ensuring that the parents of all children found to carry a haemoglobin disorder are told of the family implications, and offered carrier testing themselves.
AVAILABILITY OF CLEAR AND SIMPLE INFORMATION MATERIALS IS A PRIORITY
At risk for sickle cell disorders
At risk for thalassaemias
All haemoglobin disorders
3163
855
4018
229
475
704
7
56
18
3565
780
4355
457
425
882
13
54
20
The information presented here shows that the health system can be a barrier, rather than mediating genetic information to the public. An adequate infrastructure for genetic screening and counselling is lacking in many areas, and there is a shortage of information materials to help health professionals in informing carriers. People who are found to have a genetic risk need exactly the information that is relevant to them, at that particular time. Thus all the following are needed, and exist, for the haemoglobin disorders.
60
Current Paediatrics Primiparae: GP
Counselling
Booking
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25
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20 ]
20
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9
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Counselling 25
20
== 2O
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9
11
13
15
17
19
1
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5
7
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11
13
15
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1
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5
7
9
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13 15 17 19
Fig. 3 Gestation at three critical steps in antenatal screening for haemoglobin disorders (first visit to the GP, booking for antenatal care, and counselling) in 31 women at risk for having children with a sickle cell disorder. Those having prenatal diagnosis are shown in black. Most at-risk couples are identified and counselled in their first pregnancy. Forprimiparae, mean interval from seeing the GP to counselling was 7~ weeks and mean gestation at counselling 19 weeks: none requested prenatal diagnosis. (Three did not attend for counselling, including two whose risk was identified only when an affected child was detected by neonatal screening. The risk of an affected child being one in four, around six further couples may have been 'missed' because a carrier mother did not attend for counselling, or her partner was not tested.) The majority of multiparous at-risk women are aware of risk. Most attended their GP early and two were referred for prenatal diagnosis at this stage. The average interval to counselling for the rest was 6 weeks, when three more just achieved a first trimester diagnosis. Four did not attend for counselling, including the two referred by their GP for prenatal diagnosis. In all, one of 10 affected pregnancies was detected prenatally and terminated.
• General information for the public and for pregnant women. • Posters and leaflets to encourage carrier testing. • Diagnosis-specific information for the carriers identified. • Information for couples where both partners have been tested.* • Complete information for at-risk couples. • Information for patients and families about each disorder and its treatment. • Guidelines for doctors on treatment and prevention. • Guidelines for service planners. In fact, all the above have existed for haemoglobin disorders for years, but only the last three have been published. The remainder, though needed in large numbers, have not been printed and counsellors up and down the country have created their own leaflets. Even so, problems of dissemination mean that many patients do not receive them. New approaches based on information technology, and close collaboration between paediatricians and haematologists, are essential to ensure that families and patients are fully informed.
CONCLUSION Every year in the Whittington hospital, and in other London hospitals, seven to ten new patients with sickle cell disorders are diagnosed annually. This represents an increasingly difficult burden for patients, their families and the health service. If the prevention programme is to improve, paediatricians, obstetricians, haematologists, haemoglobinopathy counsellors, and general practitioners need to be aware of the importance of these disorders, and contribute to provision of appropriate screening and information for families. In the out-patient setting, as paediatricians see children with their parents, there is an important opportunity to inform and investigate families in relevant ethnic groups, even when a consultation is unrelated to issues of haemoglobin disorders. This is particularly important when a blood test incidentally suggests a thalassaemia or sickle cell trait. In the inpatient setting, when investigating a child in a relevant ethnic group, a haemoglobinopathy screen should become routine. REFERENCES
*There are many types of haemoglobin disorders and every combination can occur. Specific information is needed for each carrier combination, so 70 different leaflets are required.
1. Serjeant G R. Sickle Cell Disease, 2nd edn. Oxford: Oxford University Press, 1992. 2. Department of Health. Report of a Working Party of the Standing Medical Advisory Committee on Sickle Cell,
Impact and future of screening for haemoglobin disorders 61
3. 4.
5.
6.
7.
8. 9.
10.
Thalassaemia and other Haemoglobinopathies. London: HMSO, 1993. Cao A Rosatelli M C. Screening and prenatal diagnosis of the haemoglobinopathies. Bailli6re's Clinical Haematology 6. 1993: 263-286. Modell B, Petrou M, Layton M, Yarnavides L, Slater C, Ward R H T, Rodeck C, Nicolaides K, Gibbons S, Old J. Audit of prenatal diagnosis for haemoglobin disorders in the United Kingdom: the first 20 years. In press: British Medical Journal 1997; 315: 779-784. Cao A, Gabutti V, Galanello R, Masera G, Modell B, Di Palma A, Piga A, Vullo C, Wonke B. Management protocol for the treatment of thalassemia patients 1997. Obtainable from the Thalassemia International Federation, PO Box 8807, Nicosia, Cyprus. Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, Pokiti R Durazzi S M T, Muretto P, Albertini F. 1990. Bone marrow transplantation in patients with thalassaemia. The New England Journal of Medicine 1977; 322: 417421. Petrou M, Brugiatetli M, Old J, Ward R H T, Kwai Peng Wong, Modell B. Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extractioI1 for alpha thalassaemia trait. British Journal of Obstetrics and Gynaecology 1992; 99: 985-989. Health Education Authority. Sickle cell and thalassaemia: achieving health gain - guidance for commissioners and providers. In press: Guidelines for control of haemoglobin disorders. Unpublished document of the WHO. WHO/HDP/HB/GL/94.1 Obtainable free of charge from the Hereditary Diseases Programme, WHO, Geneva, Switzerland, 1994. Modell B, Anionwu A. Guidelines for screening for haemoglobin disorders: service specifications for low- and high-prevalence district health authorities. In: Ethnicity and
11.
I2. 13.
14.
15.
16. 17.
18. 19.
Health: Reviews of Literature and Guidance for Purchasers in the Areas of Cardiovascular Disease, Mental Health and Haemoglobinopathies. NHS Centre for Reviews and Dissemination/Social Policy Research Unit, CRD Report 5, ISBN No 1 900640 00 7, 1996. Old J M, Ward R H T, Petrou M, Karagozlu F, ModelI B, Weatherall DJ. First-trimester fetal diagnosis for the haemoglobinopathies: three cases. Lancet 1982; 2: 1413-1416. Petrou M, Modell B. Prenatal screening for haemoglobin disorders. Prenatal Diagnosis 1995; 15: 1275-1295. Modell B. EC Concerted action on developing patient registers as a tool for improving service delivery for haemoglobin disorders. In Health Services Research. Eds G N Fracchia, M Theophilaton. Amsterdam: IOS Press, 1993. Anionwu E N. Ethnic origin of sickle and thalassaemia counsellors; does it matter? In: Research in Cultural Differences in Health. Eds D Kelleher, S Hillier. Routledge, London & New York. 1996; 8: 160-189. Monzouras M, Camba L, Ioannou P, Modell B, Constantinides P, Gale R. Thalassaemia as a model of recessive genetic disease in the community. The Lancet 1980; 2: 574-578. Darr A, Modell B. The frequency of consanguineous marriage among British Pakistanis. Journal of Medical Genetics 1988; 25: 186-190. Prenatal diagnosis and genetic screening; community and service implications. A report of the Royal College of Physicians. The Royal College of Physicians of London, London, 1989. Neuenschwander H, Modell B. The process of antenatal sickle cell screening at a North London Hospital. Submitted for publication British Medical Journal 1997; 315: 784-785, Petrou M, Brugiatelli M, Ward R H T, Modell B. Factors affecting the uptake of prenatal diagnosis for sickle cell disease. Journal of Medical Genetics 1992; 29: 820-823.