PRACTICAL DISEASE MANAGEMENT

Dis Manage Health Outcomes 2001; 9 (6): 295-304 1173-8790/01/0006-0295/$22.00/0 © Adis International Limited. All rights reserved.

Sickle Cell Disease Screening Programs Integration Into Managed Care Sally C. Davies and Lola Oni Haematology Department, Central Middlesex Hospital, Park Royal, London, England

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Inheritance and Pathophysiology . . . . . . . . . . . . . . . . . . . . 2. The Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Laboratory Technology . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Models of Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Neonatal Screening . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Antenatal Screening . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Pre-Anesthetic Testing . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Cascade Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Opportunistic Testing . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 School/Pre-Marriage Testing . . . . . . . . . . . . . . . . . . . . 5. Implications of Screening for Sickle Cell Disease for Managed Care 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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295 296 296 297 297 298 299 300 300 300 301 301 303

Screening programs for sickle cell disease, when effective, can reduce morbidity and mortality as a direct consequence of patient education and optimized clinical management. However, informed patient or parental consent is necessary prior to the screening process as a person’s sickle status is genetic information which can, when poorly communicated to clients, lead to harm. Screening programs are at their most effective when the full process is linked, including pre-screening information for clients available in an appropriate format, continuing education for health professionals, and effective post-result education with specialist follow-up for those affected by sickle cell disease. Effective handling, storage and retrieval of results is important for patients and professionals alike, yet this remains a major problem in most healthcare organizations. This problem is maximized because of the great variety of settings, professionals and groupings that are involved in a comprehensive screening program. Managed care programs need to review the genetic risk relating to sickle cell disease for the populations they serve in order to consider whether to develop programs that are universal in coverage or targeted, depending on the most costeffective approach. In areas where the population is almost solely of North European origin and therefore where the sickle gene is rare, targeted programs are appropriate with linkage for provision of educational materials and specialist follow-up to other centers with greater experience.

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Screening is the testing not of carefully selected population samples but of apparently healthy volunteers from the general population, for the purpose of separating them into groups with high and low probabilities of the occurrence of a given disorder. Tests screening positive need formal identification for genetic counselling and clinical care. In considering the role of screening for sickle cell disease (SCD) and its integration into programs of managed care, the issues that must be clearly addressed are those of cost effectiveness, benefits, harm and limitations. The individual’s response to screening will depend on their own prior and subsequent education and requires their informed consent. This article presents the inheritance and clinical problems related to SCD as the background for screening programs. The various program models, issues relating to the model types and the implications for managed care are discussed. 1. Inheritance and Pathophysiology SCD is a family of inherited disorders of hemoglobin, having in common either the inheritance of 2 sickle β-globin genes, giving rise to the homozygous state βSβS, known as sickle cell anemia (SS), or inheritance of one sickle gene with another β-chain variant, such as hemoglobin C, giving rise to sickle hemoglobin C disease (SC). Co-inheritance of the sickle gene with a quantitative defect of βglobin chain production, such as β-thalassemia (βThal), gives rise to sickle β-thalassemia (Sβ0Thal or Sβ+Thal). Carriers have one normal β-globin gene (βA) and an abnormal βS gene, giving rise to the sickle cell trait (AS), and are healthy throughout life. SCD is inherited in a Mendelian recessive manner such that healthy carrier parents have a 1 in 4 risk, in each and every pregnancy, of conceiving an affected child. Although sickle and other hemoglobin mutations occur by chance, they have persisted in the population because of the advantage which carriers have against falciparum malaria.[1] The sickle gene is therefore found most commonly in people whose ancestors originate from historically endemic ma© Adis International Limited. All rights reserved.

Davies & Oni

laria zones. As a result of population movement and intermarriage, the hemoglobinopathies are among the most common genetic conditions worldwide, affecting African-Americans, people from the Caribbean, subSaharan Africa, Arabia, India, and the Mediterranean. There are over 60 000 AfricanAmericans with SCD in the US, and over 12 000 in the UK (with the majority of UK patients of African and Caribbean origin).[2] The substitution of valine for glutamic acid, at the sixth amino acid of the β-globin chain accounts for the pathophysiology of sickle hemoglobin. When deoxygenated, sickle hemoglobin molecules polymerize and distort the red blood cell from a flexible biconcave disk to a stiff crescent or sickle shape. With reoxygenation, the hemoglobin depolymerizes and the red blood cell reverts to its original biconcave shape. However, over time, as a result of repeated cycles of sickling and unsickling, the red cell membrane is irreversibly damaged and the red cell life span is dramatically reduced from 120 days to between 7 and 15 days.[3] 2. The Clinical Picture The hallmark of the disease is a ‘painful crisis’ due to small vessel occlusion by sickled red blood cells. This also gives rise to chronic organ damage over time. Common precipitating factors for sickling of the red blood cells are hypoxia, acidosis, increase in blood viscosity due to dehydration, chilling of the body, infection, pyrexia and stress. Sickling occurs readily in the spleen, in patients with hemoglobin SS. Functional asplenia within the first year of life is common, with a consequent high mortality related to infection with encapsulated bacteria, in particular Streptococcus pneumoniae.[4,5] SCD is very variable, such that some patients experience few clinical problems while others seem barely to be able to support a normal life. Some 13% of affected children die within the first 20 years of life, with the highest rate of mortality occurring in the first 3 years if comprehensive care including penicillin prophylaxis is not offered.[6] With neonatal or early screening and appropriate care for children, the mortality rate is much lower. Dis Manage Health Outcomes 2001; 9 (6)

Screening Programs for Sickle Cell Disease

The median life expectancy is in the mid-forties for those with hemoglobin SS.[7] The clinical management of patients with SCD is predominantly supportive,[8] aimed at preventing and treating painful crises and other complications. Patient and carer education plays an important role. In infants and children, pneumococcal prophylaxis with daily penicillin, anti-pneumococcal vaccine and anti-hemophilus influenza B vaccine with regular boosters helps to prevent associated infection and its consequences. Painful crisis is treated with analgesia, rest and fluids to correct dehydration. Other clinical complications may require the use of antibacterials, oxygen therapy and, less commonly, blood transfusion either as an exchange transfusion or as a top-up.[9] To date, the only cure for SCD is bone marrow transplantation, which has been successfully undertaken in over 200 children with a reported death rate of 6% and rejection rate of under 10%.[10] Hydroxyurea, an oral chemotherapeutic agent, has also been shown to be effective in reducing painful vaso-occlusive crisis in adults[11] and is under study in a number of pediatric centers. Other novel approaches under trial include therapies aimed at preventing red cell dehydration such as hypermagnesemia[12] and the use of clotrimazole.[13] People with AS have no related anemia or joint pains and have a normal life expectancy. There should therefore be no discrimination by employers, health insurance organizations or mortgage companies against carriers. The few such problems that we have encountered have been resolved with appropriate education of the organization. 3. Laboratory Technology Screening and testing for hemoglobinopathies is performed using venous anticoagulated blood samples or, in neonates, using dried capillary samples spotted onto filter paper. Sickle hemoglobin is detected by biochemical methods and diagnosis requires a combination of hemoglobin electrophoresis or chromatography techniques confirmed by a positive sickle solubility test, with the red cell indices and chromatography when indicated.[14] © Adis International Limited. All rights reserved.

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Screening tests for the hemoglobinopathies have high sensitivity and specificity and the tests are not expensive. The appropriate method is dependent on the age of the population to be screened as well as on the staffing and financial resources available to the laboratory. However, the detection of sickle hemoglobin presents no problem when it is present in amounts greater than 5%; either isoelectric focusing (IEF) or high performance liquid chromatography (HPLC) may be used. Infants under 1 year of age may have a negative sickle solubility test, so this has no place in neonatal screening programs. Since SCD is the result of a genetic mutation, the diagnosis once properly made cannot change throughout life although, over the first few years of life, the proportions of sickle and fetal hemoglobins do vary as a result of gene switching. 4. Models of Screening Screening programs should be population based. They can be established as universal, covering the whole population, or selective so that people satisfying certain parameters are screened; the latter programs are often known as ‘targeted programs’. The ethnic origin of an individual or group is generally used to determine whether there is a high or low risk of inheriting the sickle gene. This information is used to determine who to target for testing in a selective program. However, over time, ethnicity is proving less effective as a predictor of genetic risk. Mixed parenting in North America, the UK and many other parts of the world will eventually necessitate changing from targeted to universal screening policies, except in areas where there are people of pure Northern European origin, a situation which would be difficult to verify. Selective screening saves laboratory test costs but there are higher associated costs resulting from the selection process per se. The process relies on professionals to make a correct judgment about the ‘ethnicity’ of an individual. This leaves room for error, and failure to identify an ‘at risk’ case or pregnancy can and often does lead to litigation in the UK. Population screening programs can be Dis Manage Health Outcomes 2001; 9 (6)

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Table I. Summary of timing and purpose for population screening programs for sickle cell disease undertaken at various stages of life Screening period Neonatal

Pregnancy

School/Pre-marriage

Pre-general anesthetic

Cascade screening

Opportunistic

Purpose To identify those with disease and enrol infant into program of comprehensive care early, so as to prevent mortality and reduce morbidity To give opportunity for informed genetic choice, offer access to prenatal diagnosis and, where acceptable, termination of an affected fetus To inform population of their genetic inheritance and the possible consequences, and to enable premarital decision making To reduce mortality and morbidity in patients with sickle cell disease by proper oxygenation and hydration peri- and per-operatively To find other affected family members, so as to enable access to education and genetic choices To find mildly affected patients with disease states and advise them on the genetic and health risks

undertaken at a variety of times during life for different purposes (table I). Central to the success of the screening program is the level of awareness and the understanding of the general community about SCD, the process for giving negative and positive results to clients and the offer of genetic counseling. Where a disease is diagnosed, counseling about the health and social implications of living with the condition need to be made available, and facilities for appropriate health and social care need to be in place. Systems for both initial and continuing education of health professionals as well as easy access by the patient to specialist consultation need to be established prior to developing screening programs. All programs established to screen for SCD should be monitored continuously, in particular for uptake, coverage, results, timeliness, ‘near misses’, complaints and comments, in order to monitor that the programs are actually accomplishing their aims. 4.1 Neonatal Screening

Neonatal screening is mandated by law in the majority of states in the US.[15] In the US and UK, © Adis International Limited. All rights reserved.

neonatal screening for sickle hemoglobin is provided alongside screening for other inherited disorders, including phenylketonuria and hypothyroidism. Most laboratories use HPLC or IEF, both of which are technologically satisfactory. Studies in our laboratory have demonstrated little difference in cost between IEF and HPLC programs in terms of average cost per baby tested. In addition, it is clear, as for most laboratory tests, that there are economies of scale for programs as shown in figure 1, where only at 25 000 births tested per year does the curve begin to flatten.[16] The fluctuations in the HPLC curve reflect the annual equivalent costs of a new HPLC analyzer at intervals of 25 000 tests. While the cost per baby screened is constant, it is important to consider the cost per baby diagnosed with SCD or AS, which naturally depends on prevalence, as demonstrated in figure 2. When making a decision as to whether to fund targeted or universal programs, other issues to be considered include: the failure rate of targeted programs (which is estimated at 30% of those at risk not tested),[17,18] testing of those considered not truly at risk (which probably is also approximately 30%), and issues of rationing and equity. There are important issues relating to consent for testing that are common to all neonatal screening programs. In North America and the UK, parental consent is deemed sufficient for sampling and screening. The best time to start the process of informing the mother is during the antenatal period when ideally educational aids such as leaflets and videos should be made available. Informed consent should also explain what information will be returned to the family and the follow-up process. Patterns of service vary as to the transmission of carrier results to parents. We believe that such genetic data should be given to the family along with supportive education to help them understand its implications and a card stating the result, date, child’s details and testing laboratory. In our program, the nurse specialists have counseled over 90% of families of infants with SCD or AS and have encountered few problems, despite occasional cases of nonpaternity.[2] Dis Manage Health Outcomes 2001; 9 (6)

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10

IEF HPLC

9 Cost per baby tested (£)

8 7 6 5 4 3 2 1 0 0

50

100

150

200

250

300

350

400

450

Number tested (thousands)

Fig. 1. Comparison of average costs (1995 values) per baby tested for sickle hemoglobin using isoelectric focusing (IEF) and high

performance liquid chromatography (HPLC) [from Davies et al.,[2] with permission]. The data displayed include all laboratory costs (proportion of staff annual productive hours, consumables, annual equivalent costs of capital and both laboratory and hospital overheads) and exclude the costs of sample collection, transport and case follow-up.

4.2 Antenatal Screening

There is a wide disparity in the rates of uptake of prenatal diagnosis and termination of fetuses with SCD reported in the literature. Our work in London, UK,[19] has clearly demonstrated that this is because two very different populations are described. The first group comprises the tertiary referral population, who generally access the service through one of two possible routes: through previous contact with the tertiary center or after having been referred from a primary source, such as a sickle cell/thalassemia center. By nature, this group have already shown an interest in progressing along this path; otherwise they would not have been referred to the tertiary center. The second group are those who access the primary/community service and receive genetic counseling and for a variety of reasons, a significant proportion decline the offer of prenatal diagnosis, making the uptake rate considerably lower than among those attending the tertiary center. This variation in uptake is demonstrated in a review of the literature shown in table II. With an active sickle hemoglobin counseling service delivered either by nurse specialists or ge© Adis International Limited. All rights reserved.

netic associates, as is available in the UK, we have demonstrated that 83% of women with AS or SCD attended for counseling and that 77% of their partners were tested.[2] There appears to be a low uptake of prenatal diagnosis among those with a fetus at risk of SCD, whilst there is a high uptake of diagnosis and subsequent termination of an affected fetus among those at risk of having a child with β-thalassemia major. This low uptake of prenatal diagnosis for those at risk of having a child with SCD indicates that there is true informed genetic choice, which we believe is a good outcome of the program. Nonetheless, it is likely, based on our costing modeling, that many antenatal screening programs will become self-financing and cost effective. This is because the savings on service costs for patients born are greater than the detection costs of an affected fetus and termination, when ≥2.5% of the population carry a hemoglobinopathy trait and when half or more of those carry a β-thalassemia trait. In addition, as our calculations make no allowance for the health and social benefits of screening, genetic choice and better treatment, we conclude that the cost effectiveness of antenatal screening is not very Dis Manage Health Outcomes 2001; 9 (6)

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5000

Annual no. of births:

4500

5000 10 000 25 000 50 000 100 000

Identification cost (£)

4000 3500 3000 2500 2000 1500 1000 500 0 0

5

10

15

20

25

30

35

40

45

50

55

60

65

Trait rate

Fig. 2. Relationship of the prevalence of sickle cell trait (i.e. carriers) [per 1000 births] and the annual number of births in the program

versus the cost of sickle cell trait identification (isoelectric focusing model universal) [from Davies et al., [2] with permission]. The data displayed include all laboratory costs (proportion of staff annual productive hours, consumables, annual equivalent costs of capital and both laboratory and hospital overheads) and exclude the costs of sample collection, transport and case follow-up (1995 values).

sensitive to the estimate of the numbers choosing termination of pregnancy.[2] Women who themselves have SCD have an increased risk of miscarriage, premature delivery, undersized infants and still births as well as other complications during pregnancy. It is therefore important that these women are offered careful antenatal follow-up by both an experienced obstetrician and a doctor specializing in the care of SCD. 4.3 Pre-Anesthetic Testing

With optimal modern general anesthetics, there is no significant oxygen desaturation during induction or recovery so the sickle carrier status of patients should be irrelevant. However, anesthetists often prefer to know the sickle carrier status of a ‘racially at risk’ patient prior to an operation and arrange for hyperoxygenation during induction and inhaled oxygen during the recovery phase. Most programs in this category are targeted, related to the patient’s ethnic origin and exclude people of supposed pure Northern European origin. Occasionally, clinically ‘silent’ cases of SCD are found in this way and specialist advice and support is then needed. © Adis International Limited. All rights reserved.

4.4 Cascade Testing

Cascade testing is where one or more family members have been diagnosed and the rest of the nuclear and extended family are offered testing in order to identify those with a carrier state who are potentially at risk of having a child with a major disease in the future. The aim is to offer carriers genetic counseling for future genetic choices. The second objective is to identify those with a major disease who may be undiagnosed and who are therefore not receiving crucial medical care or have not been given information necessary to promote self care and prevent complications. Education and informed consent are important. 4.5 Opportunistic Testing

This is often employed in a primary care setting when patients attend for their first visit to a general practitioner’s surgery, a Well Man or Woman clinic, or as part of a pre-employment health check. Testing is offered to identify those with a hemoglobinopathy, the result is placed on the individual’s medical records for future reference and they are offered genetic counseling on the possible health, genetic and social implications of their result. Other opportunities for testing arise during health awareness Dis Manage Health Outcomes 2001; 9 (6)

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campaigns; for example, in universities, places of worship and other social settings. Other individuals visit their local walk-in specialist center where testing is available without a referral and, in the UK, without charge to the individual.

ever, they do not have to disclose the actual result to the priest; confidentiality is thus maintained. As a result, very few women in Cyprus carry a βthalassemia major fetus to term unknowingly; where this has occurred over the last decade it has been because of parental choice.[26]

4.6 School/Pre-Marriage Testing

Model programs have been described where screening has been offered in school as part of a biology or genetics course.[25] Another approach has been that of the Greek Orthodox Church in Cyprus, where the priest requests a certificate of testing prior to agreeing to conduct the marriage ceremony. The certificate is evidence that the couple have been tested and that where an abnormality is found they have been counseled about the possible implications of the hemoglobinopathy. How-

5. Implications of Screening for Sickle Cell Disease for Managed Care Clearly there is no gain if people, once tested, are not made aware of their results and counseled as to the implications of the result and processes are not put in place to ensure that the result is accessible to relevant health professionals who may need to offer the individual future healthcare. Ideally, the information should be retained in the patients’ general practitioner surgery or primary care

Table II. Comparison of reported results from antenatal screening programs for hemoglobinopathies Parameter

UK

US

CMH Greengross et al.[19]

Petrou et al.[20,21] Schoen et al.[22]

Rowley et al.[23]

Rowley[24]

community

referral

referral

community

community

community

Total pregnancies

22 824

NR

NR

54 700

18 907

586 000

Pregnancies with hemoglobinopathy

1688 (7.4%)

101

NR

1019 (1.9%)

810 (4.3%)

NR

Pregnant women counseled

1445 (86%)

100

NR

NR

551 (68%)

NR

Partners tested

1192 (82%)

97

NR

804

315 (57%)

NR

Total ‘at risk’ pregnancies

140 (12%)

88

NR

81 (10%)

77 (24%)

NR 6563a (1.1%)

Sickle cell disease (SCD) number at risk of SCD

111 (79%)

78 (89%)

188

NR

40a

number undertaking PND

16 (14%)

35 (45%)

109 (58%)

12a (30%)

12a (14%)

272 (4.1%)

number affected

4

10

NR

3

3

68a

number choosing TOP

3

6

NR

0

0

24a NR

β-Thalassemia (βThal) number at risk of βThal

22 (16%)

9 (10%)

NR

16a

NR

number undertaking PND

19 (86%)

6 (67%)

NR

8a (50%)

NR

NR

number affected

4

4

NR

2

NR

NR

number choosing TOP

4

4

NR

2

NR

NR

number at risk of αThal

NR

NR

NR

16

NR

NR

number undertaking PND

NR

NR

NR

8a

4

NR

number affected

NR

NR

NR

2

1

NR

number choosing TOP

NR

NR

NR

2

1

NR

number of other hemoglobinopathies

NR

NR

NR

9a

12

NR

α-Thalassemia (αThal)

a

Calculated from data provided.

CMH = Central Middlesex Hospital; NR = not reported; PND = prenatal diagnosis; SCD = sickle cell disease; TOP = termination of pregnancy.

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records since this disorder is life long and follows the patient irrespective of where they register in the future. Developing appropriate systems for information handling and storage requires input from many groups of professionals and can be hard to achieve. If a proper system is established for documenting results, a single test should, for most people, suffice as that result will remain unchanged throughout life. The important elements of such a system are to develop educational leaflets for pre-screening, to enable individuals to consider the possible sociocultural implications of being tested and being found to have a positive result. The pre-screening system needs to incorporate a patient consent form for testing, with more detailed leaflets to accompany the results post-screening. Of course, all educational materials need to be provided in an appropriate language, as English may not be understood; materials should also allow for those who cannot read. Developing such materials is helped by involving not only specialists in SCD but also health promotion experts and the appropriate community. Where the sickle gene is found, the genetic implications for those of child-bearing age or younger need full explanation, and this is best done through ‘face to face’ contact with trained health professionals. Most states in the US have mandatory neonatal screening for SCD; this means that managed care programs covering children need a system for collecting the results and, as required, informing local statutory care agencies. Individual states decide their own policy as to when and where to repeat the test for babies in their area. They also develop systems linking the laboratories that generate the results or the center distributing these results to other services so that the relevant workers can gain easy and accurate access to the appropriate results. Whichever route is chosen, the timing needs to be carefully considered as it is important to start penicillin prophylaxis for infants before they reach 3 months of age. Once diagnosed as having SCD, babies should be entered routinely into a comprehensive care pro© Adis International Limited. All rights reserved.

Davies & Oni

gram which incorporates the education of the child’s parents and carers, commencement of pneumococcal prophylaxis, provision of analgesia for pain episodes and arrangements for treating acute events. It is clear that good comprehensive care programs not only minimize complications and anxiety in the families but also help families to develop better coping strategies so that patients require fewer hospital admissions and consequently probably experience less serious morbidity. Women should be offered information, testing and genetic counseling pre-pregnancy. Whenever possible, when a hemoglobinopathy is found, the partner should be offered testing. In many managedcare programs it is possible to introduce testing for SCD into routine health checks as mentioned earlier, for example, at family planning clinics and Well Woman clinics. If the result is already available on the patient’s notes then a repeat blood test is not indicated but the education and counseling process should be repeated in order to reinforce previous information and ensure full understanding. At first diagnosis of pregnancy, health records should ideally be reviewed and women should be offered testing if no result is available on their health records. Those that have a hemoglobinopathy should be counseled regarding their genetic risk, the need to arrange for their partner to be tested and the possible consequences if their partner has a positive result. At-risk couples need to be given opportunities to access prenatal diagnosis where appropriate and, if desired, subsequent termination of an affected fetus. As in neonatal screening, there is a time factor in antenatal screening because research has clearly demonstrated that the later in pregnancy that a fetus is determined to be at risk of SCD the less likely the woman is to opt for prenatal diagnosis. It is therefore imperative to identify an ‘at risk’ couple early enough to aim for a first trimester diagnosis.[20] All educational materials should be prepared by and genetic counseling given by appropriately trained health professionals. The principles of genetic counseling should be applied, including actDis Manage Health Outcomes 2001; 9 (6)

Screening Programs for Sickle Cell Disease

ing in the client’s best interest, respecting their culture, beliefs, values and autonomy and maintaining a non-directive approach so as to enable the client to make an informed choice. Managed-care programs should also consider screening their client population and educating them at various other times including enrolment into the program or at certain life stages, for example, school leavers and college entrants. 6. Conclusions Undoubtedly, testing, counseling and repeated education of individuals reinforces their knowledge and contributes to increasing community awareness, such that individuals may consider this information when selecting a partner or prior to having children. Women will present earlier in pregnancy and are more likely to exercise their right to access prenatal diagnosis and termination of an affected fetus if they wish.[21] Where an affected child is born, counseling and education about the condition will empower the parents and increase their awareness of situations where medical intervention is required, thus reducing potential mortality, morbidity and handicap. The development of integrated screening programs for SCD by managed-care organizations in the US represents a major opportunity to improve patient care and important outcomes of quality of life and life expectancy for patients, as well as offering genetic choice to couples at risk of having a child with SCD.[23,24] These are all important endpoints but their achievement requires more than an effective pathology laboratory. Health education materials need to be prepared or sought and complex patient journeys need to be thought through and simplified to ensure easy specialist access for patients. The completion, storage and handling of patient records is a major issue that requires local solution. Any change-management process to introduce a screening program needs embedded ongoing professional education and, in addition, would benefit from the development of agreed multidisciplinary protocols and standards that can be audited for effectiveness and achievement. © Adis International Limited. All rights reserved.

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Acknowledgements This work was part funded by Grant 93/33/3 of the NHS R&D Health Technology Assessment Program, England.

References 1. Nagal RL, Fleming AF. Genetic epidemiology of the beta gene. Baillieres Clin Haematol 1992; 5: 331-65 2. Davies SC, Cronin E, Gill M, et al. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research. Health Technol Assess 2000; 4 (3): 1-99 3. Embury SH, Hebbel RP, Mohandras N, et al., editors. Sickle cell disease – basic principles and clinical practice. Philadelphia (PA): Lippincott Raven Press, 1994 4. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ 1995; 311: 1600-2 5. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anaemia. N Engl J Med 1986; 314: 1593-9 6. Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Paediatrics 1989; 84: 500-8 7. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease – life expectancy and risk factors for early death. N Engl J Med 1994; 330: 1939-43 8. Davies SC. Oni L. Management of patients with sickle cell disease. BMJ 1997; 315: 656-60 9. Davies SC, Roberts-Harewood M. Blood transfusion in sickle cell disease. Blood Rev 1997; 11: 57–71 10. Walters MA, Storb R, Patience M, et al. Impact of bone marrow for symptomatic sickle cell disease: an interim report. Blood 2000; 95 (6): 1918-241 11. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anaemia. N Engl J Med 1995; 332: 1317-22 12. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 1997; 100: 1847-52 13. Brugnara C, Gee B, Armsby CC, et al. Therapy with oral clomiprazole induces inhibition of the Gardes channel reduction of erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 1996; 97 (5): 1227-34 14. British Society for Haematology. Guidelines for haemoglobinopathy screening. Clin Lab Haematol 1988; 10: 87-94 15. Sickle Cell Disease Guideline Panel. Sickle cell disease: screening, diagnosis, management, and counselling in new-borns and infants. Clinical practice guideline no. 6. Rockville (MD): US Department of Health and Human Sciences, 1993 16. Cronin EK, Normand C, Henthorn JS, et al. Costing model for neonatal screening and diagnosis of haemoglobinopathies. Arch Dis Child 1998; 79: F161-7 17. Lane PA, Mauro RD, Houston ML, et al. Universal neonatal screening for haemoglobinopathies is more cost-effective than screening targeted to high risk infants. Presented at the Ninth National Neonatal Screening Symposium; 1992 Apr; Raleigh (NC) 18. Lane P. Targeted vs universal screening. In: Stern KS, Davis JG, editors. Proceedings of a conference on new born screening for sickle cell disease: issues and implications; 1993 Nov 6-Dec 6; Washington, DC. New York: Council of Regional Networks for Genetic Services, 1994: 157-60

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19. Greengross P, Hickman M, Gill M, et al. Outcomes of universal antenatal screening for haemogobinopathies. J Med Screen 1999; 6: 3-10 20. Petrou M, Brugiatelli M, Ward RH, et al. Factors affecting the uptake of prenatal diagnosis for sickle cell disease. J Med Genet 1992; 29: 820-3 21. Petrou M, Brugiatelli M, Old J, et al. Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian, and Mediterranean extraction for alpha thalassaemia trait. Br J Obstet Gynaecol 1992; 99: 958-9 22. Schoen EJ, Marks SM, Clemons MM, et al. Comparing prenatal and neonatal diagnosis of haemoglobinopathies. Paediatrics 1995; 92: 354-7 23. Rowley PT, Loader S, Sutera CJ, et al. Prenatal screening for haemoglobinopathies I: a prospective regional trial. Am J Hum Genet 1991; 48: 439-46 24. Rowley PT. Prenatal diagnosis for sickle cell disease. A survey of the United States and Canada. Ann N Y Acad Sci 1989; 565: 48-52

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25. Silvestroni E, BiancoI, Graziani B. First premarital screeing of thalassaemia carriers in intermediate schools in Latium. J Med Genet 1965; 15: 202-7 26. Angastiniotis MA, Hadjiminas MG. Prevention of thalassaemia in Cyprus. Lancet 1981; I: 396-71

About the Authors: Professor Sally Davies has been a consultant hematologist in North West London for 15 years, specializing in sickle cell disease. She is medical director of the sickle cell services and leads a research program around the diagnosis, clinical management and impact of sickle cell disease. Ms Oni is the Nurse Director of these services and leads the Brent Sickle Cell and Thalassaemia Centre. Correspondence and offprints: Professor Sally Davies, Haematology Department, Central Middlesex Hospital, Acton Lane, Park Royal, London NW10 7NS, England. E-mail: [email protected]

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