Pubfic Health (1990), 104, 9--20

© The Societyof Public Health, 1990

C o n g e n i t a l T o x o p l a s m o s i s : t o S c r e e n or N o t t o Screen? A. W. L. Joss*, J. M. W. Chatterton and D. O. He-Yen

Scottish Toxoplasma Reference Laboratory, Department of Microbiology, Raigmore Hospital Inverness IV2 3UJ

We have reviewed the present day quantifiable cost to society of the 73 cases of congenital toxoplasmosis which are estimated to occur annually in Scotland with the cost of preventing the disease by screening and treatment. Our analysis includes advances in laboratory techniques. The cost of screening would depend on its scale and if in-house or commercial tests are used. If only 2 specimens were screened, at booking and at delivery, the screening costs are estimated to be between 0.5q3.9 times the preventable costs. If a third specimen were tested in the second trimester, to maximise scope for remedial action during pregnancy, the screening costs are 0.7-1.2 times preventable costs. As likely screening costs in most of the schemes we consider are now less than the preventable costs, a screening programme should be adopted.

Introduction Prospective parents' expectations of modern medicine in guaranteeing a trouble free pregnancy and normal healthy offspring have never been higher. Reports of babies severely damaged in utero have encouraged a re-examination o f the case for instituting an antenatal screening service, ~'2 which would identify Toxoplasma gondii infected women or babies in time to allow appropriate preventative or therapeutic measures. T. gondii infection is usually acquired by ingestion of either encysts in the faeces o f infected cats, 3 or tissue cysts in undercooked meat. 4 Maternal parasitaemia leads to transmission to 40-50% o f foetuses, ranging from 17% in the first trimester to 65% in the third? Conversely when transmission does occur, clinically apparent infection in the newborn is much more frequent and severe in the first trimester (80%) than in the third (8%). 5 Most pregnant women in Great Britain are susceptible, but with current diagnostic practices and because maternal infections are usually asymptomatic congenital infection is grossly under recognised. 6,7 Additional impetus to the demand for screening is provided by the apparent success of comprehensive, mandatory French 8 and Austrian 9'~° programmes. N o t only are acutely infected mothers identified, but procedures have been devised to determine whether the foetus is infected and what action is appropriate for the stage o f pregnancy. H There are, however, great differences in the incidence o f toxoplasmosis in these countries compared to our own. ~2 In women at the start of pregnancy, 80% in France and 60% in Austria are immune, so few women require to be tested more than once. In Great Britain, the opposite is the case 13,14,1~with at least 80% o f women still susceptible at the start o f pregnancy. The question is whether a screening programme would be more expensive than paying for the costs o f caring for the casualties. A cost-benefit analysis published in 1984, t6 based on 1980/1 prices, firmly concluded that screening would not be o f cost benefit. Instead there was a proposal o f a health education programme to alert pregnant women o f sources of * To whom correspondenceshould be sent.

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infection. Five years later with no such programme in operation there is little evidence that public awareness o f toxoplasmosis has improved. There is now also less public tolerance for allowing preventable disease to progress undiagnosed and unchecked in utero. In this paper, we have attempted to re-analyse the relative costs in the light o f improvements in the cost efficiency o f screening techniques.

Serological Surveillance Methods In the 1980/1 analysis two alternative screening protocols were considered, the Austrian version o f Talhammer 9 and the French version o f Desmonts and Couvreur? In this paper, we likewise examine the cost and feasibility o f two approaches to screening based on modifications o f the same models. With either scheme, a positive screen result would require a follow-up blood sample two weeks later for confirmation and comparison of titres for evidence o f how recently infection was acquired. The French model might appear to be preferable because it is more comprehensive and allows infection to be identified and dealt with at almost any stage o f pregnancy. All women are tested in the second m o n t h o f pregnancy, and, if susceptible, tested again in the fifth, seventh and ninth months. Maternal infections are identified by seroconversion or by the presence o f specific IgM. In this country, booking antenatal samples are routinely submitted for syphilis and rubella serology, at two to three months gestation. Bloods which are taken for haematological testing later in pregnancy and maternal or cord bloods at delivery could be made available for toxoplasma tests. Identification o f infection before 20 weeks gestation would allow time for congenital infection to be confirmed and a choice of whether to recommend termination or drug treatment. H By the seventh m o n t h termination is no longer an option. Therefore a reasonable modification o f the French model might be to test three samples, one from the first trimester, a second midway through the second trimester and a third at the end to identify infections in the latter part o f pregnancy. The simpler protocol of Talhammer 9 involves only two blood tests, the first during the first trimester and a second, if necessary, in the eighth month. The timing o f the second specimen precludes the option o f termination. It might be as well to test maternal or cord blood at delivery. Any intervention during pregnancy would depend entirely on the detection o f specific IgM in the first specimen. Infection during the latter part o f pregnancy would prompt a thorough examination o f the neonate and treatment as soon as congenital infection was diagnosed. ~7 The previous cost-benefit analysis ~6 envisaged the use of the Sabin-Feldman dye test (DT) TM and immunofluorescence tests. ~9,2° Recently, laboratories have used enzyme-linked immunosorbent assays (ELISA) for large scale testing o f specimens, thus the IgG-ELISA and IgM-ELISA 21 from a single master dilution o f serum ~5 should form the basis for screening. Dye tests and alternative IgM assays should be reserved for confirmation o f suspected maternal infections. For neonatal sera, a more sensitive test, the IgM immunosorbent agglutination assay (ISAGA, API Bio-Merieux, Charbonnieres les Bains, France), is essential to avoid false negative results. 22 This test is too sensitive for use on maternal sera, and may detect specific IgM from infections before conception. 22 Because half o f the maternal infections do not result in foetal infection, 5 it would be essential to have the capacity in one or more Scottish Centres to carry out foetal blood sampling and amniocentesis to test for foetal infection. The French procedure H would entail: inoculation o f mice and specific IgM (ISAGA) tests for specific evidence o f infection; and white cell, platelet and eosinophil counts, total IgM measurement, lactic dehyrogenase and gamma-glutamyl transferase assays and fortnightly ultrasound examinations for non-specific evidence o f infection.

Screening for Congenital Toxoplasmosis

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After elective termination or spontaneous abortion (where toxoplasmosis was suspected), the products o f conception, placentas and foetal blood should be examined. Infected babies carried to term, together with those identified at delivery as possibly infected, would have to be followed up clinically and serologically for confirmation of congenital infection. The Costs

The cost o f a surveillance p r o g r a m m e depends almost entirely on t h e ' a n n u a l n u m b e r o f pregnancies. We agree with the assumption in the previous analysis that there is no value in screening sera from non-therapeutic terminations (although m a n y of these specimens in our experience are currently tested for syphilis and rubella). In Scotland then the annual n u m b e r to be screened at first booking would be 65,000 (the number o f births), and as only 14-17% might be expected to possess antibody, 14'~5 approximately 55,250 would require testing at subsequent visits. The preventable costs on the other hand depend entirely on the incidence of congenital toxoplasmosis. M o r e is k n o w n about this figure since the 1980/1 analysis. An eleven year study o f toxoplasmosis reported by the Scottish T o x o p l a s m a Reference L a b o r a t o r y revealed only 13 clinical cases of congenital disease, ie. 1.2 per annum. 7 Additionally, a further study ~5 of seroconversion rates during pregnancy confirmed the 0.23% figure used as the central estimated in the previous study. Incorporating the new Scottish data on reported cases as the m i n i m u m estimate, accepting the previous m a x i m u m estimate (0.8%) and averaging the two Scottish studies (0.22%) for the central figure, it is possible to determine the annual n u m b e r of clinically apparent and subclinical cases of congenital toxoplasmosis 5 (Table I). Our figures differ f r o m those of the 1980/1 analysis as we believe that analysis considered b o t h treated and untreated patients, whereas we have only considered untreated women. 5 Using the same formula as Henderson et al., 1690% of severe

Table I

Estimated annual Scottish incidence of congenital toxoplasmosis Minimum

Central

Maximum

13

143

520

Total births 65,000 Pregnant women infected: Not transmitted to foetus--49% Subclinical toxoplasmosis--36% Clinical toxoplasmosis 9% clinically severe--29% clinically mild 71% Neonatal deaths 6%

--

--

--

4.8 1.2 0.35 0.85 0.8

51.5 12.9 3.7 9.2 8.6

187.2 46.8 13.6 33.2 31.2

Mentally retarded: severe or very severe moderate mild Visually handicapped: blind moderate

0.77 0.25 0.25 0.25 1.04 0.05 0.99

8.2 2.7 2.7 2.7 I 1.2 0.56 10.64

29.8 9.9 9.9 9.9 40.6 2.0 38.6

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cases of congenital toxoplasmosis plus 8% of mild or subclinical cases are expected to be mentally retarded, one third severely, one third moderately and one third mildly. Likewise all severe and 25% of mild cases plus 10% of subclinical cases will be visually handicapped, and 5% will be blind. Preventable costs

It is difficult to update each of the estimates used in the 1980/1 analysis. This is particularly true of the medical costs. Those of in-patient or out-patient attendances have increased but they may be offset by a trend towards reducing stay in hospital or further increased by the introduction of new procedures requiring sophisticated and expensive technology. The general retail price index has increased by 58% from January 1981 to January 1989,24 and the health service price index by 64%. 25 A multiplication factor of 1.6 has therefore been applied to the preventable costs catalogued in 1980/1 and translated into Scottish terms (Table II). This formula is apparently valid for some of the listed costs. The cost of in-patient care in an acute hospital of over 100 beds, at £707 per week in Scotland for 1987/88, or £754 per week projected to the present, has risen by 54%. Many costs, however, would appear to have risen more rapidly. The weekly cost of institutional care in an average mental deficiency unit in Scotland was £268 in 1987/88, 26or adjusted to £287 for 1988/89, an increase of 86°,/o on 1980/81 figures. An estimate of the extra expense to the family of raising a handicapped child might be gauged from the current rate of attendance allowance issued by the Department of Social Security. This is £30/week and with £4/week routinely available from the Rowntree Trust for such cases, the total of £34 per week is 127% higher than the figure quoted for 1980/81. The current extra cost of special education, at least in Scotland based on 1986/87 figures adjusted to current values, would appear to have risen by 170-180°/o.27 The figures are based on the cost of special education, £6,751 per annum in 1986/87 (£7,837 in 1988/89), compared to primary, £1,042 in 1986/87 (£l,206 in 1988/89), and secondary education, £1,767 in 1986/87 (£2,050 in 1988/89). The loss of marketed output was updated to 1980/81 values by accounting for earnings inflation according to the published average earning index. Continuing the same projection to April 1989,2s this cost item could be upgraded by approximately 90%. Surveillance costs

Active surveillance implies taking all necessary and appropriate measures to counteract identified disease. Therefore the cost of antenatal screening and the cost of confirming foetal infection and resulting therapy must all be included. However, to allow direct comparison with the 1980/1 analysis, our initial estimations exclude the cost of foetal sampling which was not considered in 1980/1 (Table liD. Four schemes are costed: A, where sera are tested three times during pregnancy (at 2-3 months, at 5-6 months and at the end); B, as in A but with in-house tests; C, testing twice during pregnancy, (at 2-3 months and at the end); and D, as in C but with in-house tests. The higher estimates of screening costs (A and C) assume the use of commercial ELISA kits. All samples are tested for IgG and IgM on the first sample, but only lgM on the subsequent samples. There will be 240,500 (A) or 185,000 (C) tests at £1 per test. (The cost per test for ELISAs range from £0.80 to £1.20 depending on supplier.) For the lower estimates (B,D), in-house reagents 29,3°produced in the Reference Laboratory are used at a cost of 10 p per specimen for each test, all specimens tested in duplicate. The only other items of major expenditure involved in ELISA screens are pipette tips at 1.7 p each (2-3 per

Screeningfor Congenital Toxoplasmosis

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specimen) and microtitre plate washers (ca. £3,000 each) and readers (ca £8,000 each), with an estimated working life o f 4 years. In A and C, it is assumed that screening will be centralised in 6 laboratories in the 4 major cities of Scotland, with the reference work carried out in Inverness. Alternatively all the screening could be carried out in the Reference Laboratory, allowing some economies o f scale (B and D). The first proposal would require a total o f 6 washers, 6 readers and 12 additional personnel; the second would require a total o f 5 washers, 3 readers and 6 additional personnel. The confirmatory tests would be carried out in the Reference Laboratory. The number will depend on the positive IgM screen results at each testing. This in turn will depend on the number of true positive screen results, i.e. the number o f maternal infections, and the specificity o f the screen test. Henderson et al. 16 based their treatment costs on the procedures in practice at that time; spiramycin treatment o f pregnant women in France and pyrimethamine/sulphonamide/folinic acid in Austria. Our costs assume the more rational approach now adopted in France, 1~ so that some women would receive spiramycin only, some spiramycin followed by termination and some spiramycin alternated with antiparasitic drugs, depending on the results o f foetoscopy and their preferences regarding termination. A large cost factor would be the number of women receiving spiramycin (£33 per week at current costs) as soon as toxoplasmosis was suspected. Taking the central estimate o f toxoplasmosis incidence in pregnancy, this would include all 70 infected mothers with negative results on foetal sampling, half o f the whom might require 30 weeks treatment and the remainder 20 weeks, assuming equal numbers were identified at the end of each trimester. Assuming the same proportions opting for each procedure as in France, l~ there might be 45 terminations at £250 each, and 28 patients receiving three 3-weekly courses o f pyrimethamine, sulphadiazine plus folinic acid alternating with 3 weeks of spiramycin at a cost of£680 per patient. 3~ In addition the 45 mothers who opted for termination may have already received approximately 10 weeks o f spiramycin. Neonatal treatment (3 to 4 courses o f 21 days pyrimethamine, sulphadiazine and folinic acid, alternated with 2 or 3 courses o f 45 or 30 days respectively o f spiramycin~2), would be reserved for the 28 cases whose mothers opted not to terminate in schemes A and B, plus, in schemes C and D, half those who would have opted for termination had they been identified. In 1980/1, the costs of foetoscopy were not considered, and no estimate was made of those arising from false positive serological results. Schemes A and B would result in 143 foetoscopies at £400 each in infected mothers, and schemes C and D half that number (Table IV). The cost o f laboratory tests associated with foetoscopy have been assigned a value o f £ 10 per patient per department where the tests were carried o ut--haematology for blood and platelet counts, biochemistry for liver function tests and microbiology for specific tests. Each suspected case would receive a fortnightly ultrasound scan (£20/scan) till the end o f pregnancy. The ultimate consequences o f false positive results are, firstly, additional unnecessary foetoscopies and laboratory tests and, secondly, unnecessary spiramycin treatment for up to 25 weeks. The in-house IgM-ELISA is 94% specific. 29 Therefore in addition to the 143 true infections, 10,530 false positive IgM results from 175,500 tests would require confirmation. The costs assume the employment of 2 additional personnel to carry out the confirmatory testing and the use of commercial ELISA IgM tests at £1 each. The confirmatory IgM tests on these will generate a similar proportion o f random false positive results, so that the worst overall false positive rate would be 0.36%. If the likelihood o f a significant dye test titre occurring in this group was also 6% the rate decreases to 0.02%. In

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Congenital toxoplasmosis: to screen or not to screen?

We have reviewed the present day quantifiable cost to society of the 73 cases of congenital toxoplasmosis which are estimated to occur annually in Sco...
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