Papers

Cost effectiveness of antenatal screening for cystic fibrosis

^a Centre for Reproduction, Growth and Development, Research School of Medicine, University of Leeds, Leeds LS2 9LN, ^b Centre for Health Economics, University of York, York YO1 5DD, ^c NHS Centre for Reviews and Dissemination, University of York, York YO1 5DD, ^d Molecular Oncology, Centre for Cancer Research, University of Leeds, Leeds LS2 9JT

Correspondence to: Professor Cuckle.

Abstract

Objective: To estimate the cost effectiveness of different antenatal screening programmes for cystic fibrosis.
Setting: Antenatal clinics and general practices in the United Kingdom.
Design: Four components of the screening process were identified: information giving, DNA testing, genetic counselling, and prenatal diagnosis. The component costs were derived from the literature and from a pilot screening study in Yorkshire. The cost of a given screening programme was then obtained by summing the components according to the specific screening strategy adopted (sequential and couple), the proportion of carriers detected by the DNA test, and the uptake of screening. Baseline assumptions were made about the proportion with missing information on carrier status from previous pregnancies (20%), the proportion changing partners between pregnancies (20%), and the uptake of prenatal diagnosis (100%). Sensitivity analysis was performed by varying these assumptions.
Main outcome measure: Cost per affected pregnancy detected.
Results: Under the baseline assumptions sequential screening costs between pounds sterling40000 and pounds sterling90000 per affected pregnancy detected, depending on the carrier detection rate and uptake. Couple screening was more expensive, ranging from pounds sterling46000 to pounds sterling104000. From the sensitivity analysis a 10% change in the assumed proportion with missing information from a previous pregnancy alters the cost by pounds sterling4000; a 10% change in the proportion with new partners has a similar effect but only for couple screening; and cost will change directly in proportion to the uptake of prenatal diagnosis.
Conclusions: While economic analysis cannot determine screening policy, the paper provides the NHS with the information on cost effectiveness needed to inform decisions on the introduction of a screening service for cystic fibrosis.

Introduction

Cystic fibrosis is the most common recessive condition in the United Kingdom, with a birth prevalence of 1 in 2500,¹ implying a carrier frequency of 1 in 25. Since the discovery of the principal genetic mutations involved,^{2 3 4} antenatal screening has become feasible, and pilot studies show that it is generally acceptable in the United Kingdom.^{5 6 7 8 9} Each health authority now needs to decide whether to introduce a service. One consideration will be cost effectiveness, and in this paper we estimate this for different screening strategies and under a range of assumptions.

Methods

The aim was to estimate the cost per affected pregnancy detected. This is dependent on the screening strategy adopted, the proportion of carriers detected by the DNA test, and the uptake rate.

SCREENING STRATEGIES

The aim of screening is to identify women and their partners who are both carriers. There is then a 1 in 4 chance that the infant has cystic fibrosis, and the couple are referred for genetic counselling about having invasive prenatal diagnosis. Those offered screening require basic information about cystic fibrosis, carrier testing, prenatal diagnosis, and consequent options available to them. Carrier couples can be identified by using two different strategies.

Sequential carrier testing is offered to mothers, and a sample is requested from the partner only if the mother is found to be a carrier. Basic information is given initially to all women and subsequently to the partner of each carrier.

Couple carrier testing is offered to couples, and samples are obtained from both parents at the outset. The DNA testing, however, is done exactly as in sequential screening so that only a small percentage of samples from fathers are actually tested. The result is reported as "positive" for carrier couples, otherwise as "negative."¹⁰ This strategy removes the period of anxiety while the partner's result is awaited.

The results of a test in the first pregnancy may suffice for subsequent pregnancies unless the couple cannot remember their carrier status and it is not in the antenatal notes or there is a new partner. In our economic analysis we assume that all women have two pregnancies, the projected average family size in the United Kingdom.¹¹ In the absence of published data we made the baseline assumptions that carrier couples remember their status but otherwise 20% have missing information and that of the remainder, 20% change partners. These proportions were each then varied from 10-30% in a sensitivity analysis.

CARRIER DETECTION RATE

The proportion of carriers that can be detected depends on the specific mutations sought and their prevalence among carriers in the population. In the United Kingdom about 70-85% of carriers have the F508 mutation, and the next most common three account for a further 5-10%.^{12 13 14 15 16} In this analysis we test for F508 alone in populations where the prevalence of the mutation is 70-85% and use a multimutation test where it is 80-95%. The corresponding proportions of affected pregnancies detected are 49-72% and 64-90%, respectively.

UPTAKE

In the British pilot studies reported so far, the uptake was 78% of the 11596 women offered screening in Edinburgh,^{5 8} 85% of 623 in Manchester (H Harris, personal communication),⁶ 67% of 482 in Oxford,⁷ and 90% of 2002 in Aberdeen.⁹ Uptake was somewhat lower at 62% in our own pilot study of 6071 women in Yorkshire. In our analysis we consider rates of uptake ranging from 55% to 95%.

In the published studies few partners of carrier women refused testing, and we have assumed a 100% uptake. There are too few carrier couples in the published studies to judge how many are likely to refuse prenatal diagnosis. Therefore we made the baseline assumption that uptake is 100% and then examined the effect of reducing this by 10-20% in a sensitivity analysis.

ECONOMIC ANALYSIS

There are four components of the screening process which need to be costed separately--namely, information giving, DNA testing, genetic counselling, and prenatal diagnosis. We did not consider costs consequent on the diagnosis (for example, termination of pregnancy). A reasonable estimate was made for each component cost (at 1995 prices unless otherwise stated).

Information giving--In the Yorkshire pilot study, as in Edinburgh,^{5 8} a printed leaflet backed up by a face to face interview with a midwife or general practitioner was found to be adequate. The number of women that can be seen by a given midwife will depend on the length of the interview, interval between interviews, paperwork, and other related duties. We timed the midwife interview for 31 women, and on average it lasted 11 minutes, which is similar to the 10 minutes found for the interviews with general practitioners in Manchester.⁶ If we consider all factors together, a half time midwife would suffice for the additional workload in an obstetric unit with 5000 patients annually. This would cost pounds sterling10000, or pounds sterling2 per woman. The cost of printing the leaflet is negligible.

View larger version (31K): [in this window] [in a new window]   Cost of a sequential antenatal screening programme for cystic fibrosis

DNA testing--For F508 only a relatively cheap, in house polymerase chain reaction method can be used. This was done in the Yorkshire pilot study, which had average laboratory costs during 1992-4 of pounds sterling6.70 for consumables, pounds sterling6.20 for staff, and pounds sterling3.20 for overheads, bringing the total to pounds sterling16.10 a specimen, including the cost of technical repeats and controls. As this was a research study licence fees were not paid to patent holders. The additional cost of licences for routine NHS use, however, are likely to be offset by reduced unit cost due to a higher laboratory throughput. Testing in house for multiple mutations would be more costly. At present only one set of commercial reagents is available in the United Kingdom and is fully licensed (Johnson and Johnson Clinical Diagnostics, Amersham). In Aberdeen DNA testing with this during 1993 was costed at pounds sterling23.17 a specimen¹⁷; this underestimated distributors' minimum reagent costs, which would increase the overall cost to pounds sterling33.21. For our principal analyses we have taken pounds sterling16 as the cost of DNA testing for F508 alone and pounds sterling33 when multiple mutations are sought. In the long term it is likely that the cost may fall, and a sensitivity analysis is carried out for costs in the range pounds sterling5-pounds sterling25.

Genetic counselling--We do not know of any published information on the cost of counselling couples who are carriers of cystic fibrosis. The genetics services of a region with 100000 births annually would typically need to cope with about 80 carrier couples a year. The additional counselling both before the prenatal diagnosis and when necessary after the result was known would require a genetic nurse specialist for one session. This would cost about pounds sterling2000, or pounds sterling25 per couple.

Prenatal diagnosis--The invasive procedure was taken to cost pounds sterling200, a similar figure to that adopted in recent analyses of screening for Down's syndrome.^{18 19 20} The laboratory costs are the same as for carrier testing; the costs of testing the sample for other fetal disorders such as Down's syndrome are excluded.

Results

The figure shows the calculation of the estimated cost of a sequential screening programme directed at a population of 1000000 pregnant women. In this example a F508 only test is used; the carrier detection rate is 80% and uptake is 75%. The total cost divided by the number of affected pregnancies detected yields a cost per affected pregnancy detected of pounds sterling46000.

Table 1 shows the cost for a sequential strategy with a range of different carrier detection rates and uptakes. Uptake does not have a major impact as it influences only the relatively low cost of information giving (see figure). The carrier detection rate has a much greater effect as the number of affected pregnancies diagnosed is directly proportional to the square of this rate. The rate will be higher if a multimutation test is used, but the cost per affected pregnancy detected will increase substantially. Unless the rate is more than 10% higher the marginal cost will exceed pounds sterling100000.

Table 1--Sequential screening: cost (pounds sterling000s) per affected
pregnancy detected according to carrier detection rate*
and uptake of screening
-----------------------------------------------------------------------
                                    Uptake of screening
-----------------------------------------------------------------------
Carrier detection rate          55%    65%    75%    85%    95%
-----------------------------------------------------------------------
F508 only test:
 70%                            63     61     60     59     58
 75%                            55     53     52     52     51
 80%                            48     47     46+    45     45
 85%                            43     42     41     40     40
Multimutation test:
 80%                            90     89     88     87     86
 85%                            80     79     78     77     77
 90%                            72     70     70     69     69
 95%                            64     63     63     62     62
-----------------------------------------------------------------------
*Proportion of carriers detected by DNA test.
+Example illustrated in figure.

Table 2 gives the estimated cost of a couple screening strategy. This is more expensive than sequential screening by pounds sterling6000-14000 because of the need to retest women who have changed partners, the woman's carrier status being unknown if the result from the first pregnancy is reported as negative.

Table 2--Couple screening: cost (pounds sterling000s) per affected pregnancy
detected according to carrier detection rate* and
uptake of screening
----------------------------------------------------------------------------
                                    Uptake of screening
----------------------------------------------------------------------------
Carrier detection rate          55%    65%    75%    85%    95%
----------------------------------------------------------------------------
F508 only test:
 70%                            73     71     69     68     67
 75%                            64     62     60     60     59
 80%                            56     54     53     53     52
 85%                            50     48     47     47     46
Multimutation test:
 80%                           104    103    101    101    100
 85%                            92     91     90     89     89
 90%                            83     81     81     80     79
 95%                            74     73     73     72     71
----------------------------------------------------------------------------
*Proportion of carriers detected by DNA test.

The effect of varying our main assumptions is examined in table 3. For both the screening strategies the cost increases steadily according to the proportion with missing information. There is a similar rate of increase in costs according to the proportion with new partners but only for couple screening. If the uptake of prenatal diagnosis assumed in the figure is reduced to 90% only 346 affected pregnancies would be detected and the cost would increase from pounds sterling46000 to pounds sterling51000; thus costs rise directly in proportion to the fall in uptake. The DNA test is by far the largest contributor to cost, and so variations in the unit cost of the test are influential. A reduction will lead to an almost proportionate fall in the cost of detecting an affected pregnancy (table 4).

Table 3--Cost (pounds sterling000s) per affected pregnancy detected
according to proportion with missing information* and
new partners in second pregnancy assumed in analysis+
-------------------------------------------------------------------
                                   Screening strategy
Missing                       -------------------------------------
information  New partner       Sequential       Couple
-------------------------------------------------------------------
10%             10%               42              45
10%             20%               42              49
10%             30%               42              53
20%             10%               46              49
20%             20%               46              53
20%             30%               46              57
30%             10%               49              52
30%             20%               50              57
30%             30%               50              60
-------------------------------------------------------------------
*Proportion who do not remember their carrier status in first pregnancy,
and it is not in obstetric records.
+Assumed: F508 test only, carrier detection rate is 80%, uptake is
75%.

Table 4--Cost (pounds sterling000s) per affected pregnancy detected
according to carrier detection rate,* screening strategy,
and cost of DNA test+
-----------------------------------------------------------------------------------------------------------------
                                        Cost of DNA test
Carrier detection rate            -------------------------------------------------------------------------------
and screening strategy  pounds sterling5 pounds sterling10 pounds sterling15 pounds sterling20 pounds sterling25
-----------------------------------------------------------------------------------------------------------------
70%:
  Sequential                 25               41                 57                72              88
  Couple                     29               47                 66                84             102
75%:
  Sequential                 22               36                 50                63              77
  Couple                     25               41                 57                73              89
80%:
  Sequential                 19               32                 44                56              68
  Couple                     22               36                 51                65              79
85%:
  Sequential                 17               28                 39                50              60
  Couple                     20               32                 45                57              70
90%:
  Sequential                 16               25                 35                45              54
  Couple                     18               29                 40                51              63
95%:
  Sequential                 14               23                 32                40              49
  Couple                     16               26                 36                46              56
-----------------------------------------------------------------------------------------------------------------
*Proportion of carriers detected by DNA test.
+Assumed uptake is 75%.

Discussion

We have shown that the cost of detecting a pregnancy affected by cystic fibrosis may range between pounds sterling40000 and pounds sterling104000 depending on the screening strategy, the proportion of carriers detected by the DNA test, and the uptake. Sensitivity analysis showed that cost was not greatly affected by assumptions relating to the extent to which testing is necessary in subsequent pregnancies. Of more importance was our assumption that all carrier couples accept prenatal diagnosis. In practice some will refuse, and the cost per affected pregnancy detected will increase in direct proportion.

The unit cost of the DNA test was the most important variable. The cost of screening will be lowest in centres where a high detection rate can be achieved with a DNA test for F508 only. The use of a multimutation test may considerably increase the detection rate but at present this will result in an approximate doubling of the cost of detecting an affected pregnancy.

Couple screening is more expensive than sequential screening because the carrier status of individual patients is not reported. This non-disclosure is aimed at avoiding anxiety in couples with a moderately high risk of an affected pregnancy because the mother is a carrier but the partner did not have any of the mutations tested for. Studies of sequential screening, however, have not found anxiety levels in such couples to be increased,^{5 9} and one study of couple screening found the non-disclosure to be, of itself, a source of anxiety.⁹ A form of couple screening with complete disclosure would be no more costly than sequential screening and avoid some of its anxiety.

Three previous studies have estimated the cost per affected birth avoided by antenatal screening to be about $450000-860000 depending on the screening strategy (pounds sterling284000-542000 converted by using purchasing power parity),²¹ $326000 (pounds sterling205000),²² and $1658000 (pounds sterling1043000).²³ There are four main reasons why these estimates are much higher than our own. Firstly, the cost of the DNA test was greater: $125 (pounds sterling79),²¹ $72 (pounds sterling45),²² and $100 (pounds sterling62).²³ Secondly, one study assumed that only 30% of affected pregnancies detected would be terminated.²³ Thirdly, one study included the indirect costs of travelling for the test and work loss which amounted to one third of the direct costs.²² Lastly, two studies considered screening in just one pregnancy^{21 23}: had we done so the cost would have almost doubled (for example, from pounds sterling46000 to pounds sterling76000 in the figure).

The method of economic appraisal we have adopted is a cost effectiveness analysis. An alternative approach is cost-benefit analysis, in which the benefits are also measured and valued. For example, the avoidance of treatment costs incurred by an individual patient with cystic fibrosis (estimated in 1990 to be pounds sterling8000 a year for adults²⁴) may be seen as a large benefit. The welfare or utility experienced by a person with cystic fibrosis and their family in not having to care for the affected person, or that gained by an early diagnosis even when it is decided to continue the pregnancy, are more difficult to quantify and are usually ignored. In three such studies of antenatal screening for cystic fibrosis, two concluded that benefits exceed costs provided that (in Israel) only the Ashkenazi Jews are screened²² or that the cost of the DNA test is under $130 (pounds sterling82),²⁵ while the third concluded that under most assumptions costs would exceed benefits.²³

Another approach to the economic analysis is to value the benefit to couples of knowing their carrier status, whether for its own sake or not,²⁶ by performing a willingness to pay analysis. This entails asking people how much they would be prepared to pay for the service. The results of a study in Aberdeen suggest that this is about pounds sterling18-19.²⁷ This is remarkably close to the actual cost per woman offered screening with F508 only (for example, pounds sterling18 each or pounds sterling17758000/1000000 women in the figure) but only half the cost of using a multimutation test.

The cost of screening for cystic fibrosis is higher than for established services, although not greatly so (for example, about pounds sterling30000 for screening maternal serum for Down's syndrome^{18 19 20}). Thus there are no economic grounds for not introducing a service into routine NHS practice, although there may be other social, ethical, and political reasons for not doing so.

We thank Pat Garcia for help in obtaining the times taken for information giving at the Royal Hull Maternity Hospital, Fraser Lewis for calculating the cost of DNA testing in the Yorkshire pilot study, and Dr Bob Mueller for helpful advice on counselling provision.

Funding: Department of Health and Yorkshire Regional Health Authority.

Conflict of interest: None.

1. British Paediatric Association Working Party on Cystic Fibrosis. Cystic fibrosis in the United Kingdom 1977-85: an improving picture. BMJ 1988;297:1599-602.
2. Rommens JM, Iannuzzi MC, Kerem B-S, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65. [Abstract/Free Full Text]
3. Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characteristics of complimentary DNA. Science 1989;245:1066-73. [Abstract/Free Full Text]
4. Kerem B-S, Rommens JM, Buchanan JA, Markiewice D, Cox TK, Chakravirti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80. [Abstract/Free Full Text]
5. Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, et al. Prenatal screening for cystic fibrosis. Lancet 1992;340:214-6. [Medline]
6. Harris HJ, Scotcher D, Hartley N, Wallace A, Craufurd D, Harris R. Cystic fibrosis carrier testing in early pregnancy by general practitioners. BMJ 1993;306:1580-3.
7. Wald NJ, George LM, Wald NM. Couple screening for cystic fibrosis. Lancet 1993;342:1307-8. [Medline]
8. Livingstone J, Axton RA, Gilfillan A, Mennie M, Compton M, Liston WA, et al. Antenatal screening for cystic fibrosis: a trial of the couple model. BMJ 1994;308:1459-62. [Abstract/Free Full Text]
9. Miedzybrodzka ZH, Hall MH, Mollison J, Templeton A, Russell IT, Dean JCS, et al. Antenatal screening for carriers of cystic fibrosis: randomised trial of stepwise v couple screening. BMJ 1995;310:353-7. [Abstract/Free Full Text]
10. Wald NJ. Couple screening for cystic fibrosis. Lancet 1991;338:1318-9. [Medline]
11. Office of Population Censuses and Surveys. National population projections. London: HMSO, 1995. (Series PP2 No 19.)
12. Cystic Fibrosis Genetic Analysis Consortium. Worldwide survey of the (Delta)F508 mutation. Am J Hum Genet 1990;47:354-9. [Medline]
13. Shrimpton AE, McIntosh I, Brock DJH. The incidence of different cystic fibrosis mutations in the Scottish population: effects on prenatal diagnosis and genetic counselling. J Med Genet 1991;28:317-21. [Abstract/Free Full Text]
14. Cheadle J, Myring J, Al-Jader L, Meredith L. Mutation analysis of 184 cystic fibrosis families in Wales. J Med Genet 1992;29:642-6. [Abstract/Free Full Text]
15. Miedzybrodzka ZH, Dean JCS, Russell G, Friend JAR, Kelly KF, Haites NE. Prevalence of cystic fibrosis mutations in the Grampian region of Scotland. J Med Genet 1993;30:316-7. [Abstract/Free Full Text]
16. Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascade testing for carriers of cystic fibrosis gene. BMJ 1994;308:1462-8. [Abstract/Free Full Text]
17. Miedzybrodzka ZH, Yin Z, Kelly KF, Haites NE. Evaluation of laboratory methods for cystic fibrosis carrier screening: reliability, sensitivity, specificity, and cost. J Med Genet 1994;31:545-50. [Abstract/Free Full Text]
18. Sheldon TA, Simpson J. Appraisal of a new scheme for prenatal screening for Down's syndrome. BMJ 1991;302:1133-6.
19. Shackley P, McGuire A, Boyd PA, Dennis J, Fitchett M, Kay J, et al. An economic appraisal of alternative pre-natal screening programmes for Down's syndrome. J Public Health Med 1993;15:175-84. [Abstract/Free Full Text]
20. Piggott M, Wilkinson P, Bennett J. Implementation of an antenatal serum screening programme for Down's syndrome in two districts (Brighton and Eastbourne). Journal of Medical Screening 1994;1:45-9. [Medline]
21. Asch DA, Patton JP, Hershey JC, Mennuti MT. Reporting the results of cystic fibrosis carrier screening. Am J Obstet Gynecol 1993;168:1-6. [Medline]
22. Ginsberg G, Blau H, Kerem E, Springer C, Kerem B-S, Akstein E, et al. Costbenefit analysis of a national screening programme for cystic fibrosis in a Israeli population. Health Economics 1994;3:5-23. [Medline]
23. Lieu TA, Watson SE, Washington AE. The cost-effectiveness of prenatal carrier screening for cystic fibrosis. Obstet Gynecol 1994;84:903-12. [Medline]
24. Robson M, Abbott J, Webb K, Dodd M, Walsworth-Bell J. A cost description of an adult cystic fibrosis unit and cost-analyses of different categories of patients. Thorax 1992;47:684-9. [Abstract/Free Full Text]
25. Garber AM, Fenerty JP. Costs and benefits of prenatal screening for cystic fibrosis. Med Care 1991;29:473-89. [Medline]
26. Mooney G, Lange M. Ante-natal screening: what constitutes 'benefit'? Soc Sci Med 1993;37:873-8.
27. Miedzybrodzka Z, Semper J, Shackley P, Abdalla M, Donaldson C. Stepwise or couple antenatal carrier screening for cystic fibrosis?: women's preferences and willingness to pay. Journal of Medical Screening 1995:32:282-3.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

This article has been cited by other articles:

• van den BOOM, G., van SCHAYCK, C. P., RUTTEN-van MOLKEN, M. P. M. H., TIRIMANNA, P. R. S., den OTTER, J. J., van GRUNSVEN, P. M., BUITENDIJK, M. J., van HERWAARDEN, C. L. A., van WEEL, C. (1998). Active Detection of Chronic Obstructive Pulmonary Disease and Asthma in the General Population . Results and Economic Consequences of the DIMCA Program. Am. J. Respir. Crit. Care Med. 158: 1730-1738 [Abstract] [Full text]  
• Kinmonth, A. L., Reinhard, J., Bobrow, M., Pauker, S. (1998). The new genetics: Implications for clinical services in Britain and the United States. BMJ 316: 767-770 [Full text]  
• Torgerson, D. J, Spencer, A. (1996). Methods used in economic evaluations of prenatal screening are disputed. BMJ 313: 303a-303 [Full text]  
• Seymour, C. A (1996). Controversies in Management: Screening asymptomatic people at high risk for hepatitis C. BMJ 312: 1347-1348 [Full text]  
• Doherty, R. A, Bradley, L. A, Haddow, J. E (1996). Couple screening would be easier for many centres. BMJ 312: 909-909 [Full text]  
• Brock, D. J H (1996). Cost effectiveness of antenatal screening for cystic fibrosis. BMJ 312: 908a-908 [Full text]  
• Kent, P. (1996). Counsellors do not have to be genetic nurse specialists. BMJ 312: 908b-908 [Full text]  
• Morris, J. (1996). Couple screening should be preferred for medical reasons. BMJ 312: 908c-909 [Full text]  
• Torgerson, D. J (1996). Authors should have used marginal analysis. BMJ 312: 909a-909 [Full text]  
• Walters, S. (1996). Study might be better described as a cost description of screening. BMJ 312: 909b-910 [Full text]