Idea Transcript
SAMJ ARTICLES
consequent inefficiency. This inefficiency is compounded by poor success in following up women with abnormal smears. To be effective, a screening programme should aim to maximise coverage through a systematic and efficient process, rather than increase the frequency of screening." WHO recommendations for developing countries are to aim initially to screen every woman once in her lifetime at the age of about 40 years." With greater resources the frequency of screening may be increased to once every 10 years, and then to once every 5 years for women between the ages of 35 and 55 years." The level of resources currently expended on screening in Khayelitsha indicates that services should aim initially to screen each woman once in her lifetime. This strategy's increased yield, through maximisation of coverage, will result in greater cost-effectiveness than the provision of repeat smears to a smaller number of women in order to improve the sensitivity of cytology screening. The distribution of age at presentation indicates that this screening should take place between 35 and 40 years of age. Measures to improve follow-up should be emphasised. The basic principles of primary health care (accessibility, acceptability, availability, affordability) should be applied in the quest to achieve maximum coverage, which is the first major target. Improved coverage of higher-risk groups has major implications for the organisation and provision of primary care services in similar settings throughout South Africa. We thank Shona Wilson for extracting the data for this study, and Professor Jonny Myers and Or Leslie London for reviewing early drafts of the article. REFERENCES
1. Miller A. Planning cancer control strategies. Chronic Disease in Canada 1992; 13: suppI1,51-525. 2. Paul C, Bagshaw S, Sonite R, et al. Cancer screenmg: 1991 cervical screening recommendations. NZ Med J 1991; 104: 291-295. 3. Herrero R, Brinten LA, Reeves WC, et al. Screening for cervical cancer in Latin America: a case control study. Int J Epidemiol 1992; 21: 1050-1056. 4. Bailie RS, Petrie K. Women's attitudes te cervical smear testing. NZ Med J 1990; '03: 293-295. 5. Brindle G, Wakefield J, Yule R. Cervical smears: are the right women being examined? BMJ 1976; 1: 1196-1197. 6. Mitchell H. Drake M, Medley G. Papanicolaou smears in Victoria: are the wrong women being screened? Med J Aust 1987; 147: 559-560. 7. Koopmanschap MA, Lubbe KT, Van Oartmarssen GJ, Van Agt HM, Van Ballegooijen M, Habbema JD. Economic aspects of cervical cancer screening. Soc Sci Med 1990; 30: 1081-1087. 8. London L Pap smear coverage among rural workers. S Afr Med J 1993; 83: 172-
176. 9. Hakama M. Screening. In: Holland W. Detels R, Knox G, eds. Oxford Textbook of Public Health. 2nd ed. Oxford: Oxford University Press, 1991: 102. 10. Du Toit JP. A plea for some organised planning. South African Journal of Hospital Medicine 19aO; 6: 199-205. 11. Gardon-Grant MC. Carcinoma of the cervix - a tragic disease in South Africa. S Air Med J 1981; 61: 819-822. 12 Gardan-Grant MC. Ca cervix: A crying need for extensive screening. Hospital
1987; Sep!: 36-40. have we lost the battle? S Atr Med J 1989; 76: 587. 14. Fann S, Klugman B, Dehaeck K. Towards a national screening policy for cancer of the cervix in South Africa (Paper No. 31). Johannesburg: Centre for Health Policy, Department of Community Health, University of the Witwatersrand, 1993. 15 Harrison 0, McQueen A. An Overview of Khayelitsha: Implications for Health Policy and Planning, Cape Town: Health Systems DiVision of the Centre for Epidemiological Research in Southern Africa, 1992. 16. Bradshaw 0, Batha H, Joubert G, Pretorius JP, Van Wyk R, Yach D. 7984 Review of South African Mortality. Cape Town: MRC Institute of Biostatistics, 1984. 17. World Health Organisation. Cytological Screening in the Control of Cervical Cancer: Technical Guidelines. Geneva: World Health Organisation, 1988. 18. Llewellyn-Jones D. Fundamentals of Obstetncs and Gynaecology. 4th ed. London: Faber and Faber, 1986: 184-185.
13. Cranje HS. Cervical cancer -
Accepted'6 May 1994.
Phenylketonuria in South Africa A report on the status quo H. W. Hitzeroth,
C. E. Niehaus, D. C. Brill
During the 1980s a pilot newborn screening programme for the early detection (and treatment) of amino acidopathies, especially phenylketonuria (PKU), was conducted by the Department of National Health and Population Development. The motivation for this pilot programme was the high priority accorded PKU screening in Europe and North America and the presumed similarly high incidence of this condition among South Africans of European origin. From a cohort of 59 600 newborns screened in the Pretoria area over a period of 8 consecutive years (1979 - 1986), only 1 case of PKU (and 1 of tyrosinaemia) was found. Statistically this result is compatible (Poisson distribution, 95% confidence interval) with a 'true' incidence of not more than 3/59 600 (or about 1/20000) newborns. It is concluded from this result and other relevant information that newborn screening for PKU and other amino acidopathies is not cost-effective and justifiable, especially against the background of prevailing demographic conditions and more pressing health priorities in South Africa. This particular screening programme was discontinued in 1986. The results and conclusions are presented here. for the record. S Atr Med J 1995; 85: 33-36.
Phenylketonuria (PKU) is a well-known, inherited metabolic disease. It has attained a high profile in the context of medicogenetic preventive services: because, among other reasons, it is known to cause severe and irreversible mental retardation;'·2 its incidence among newborns in western Europe and North America is such that it warrants interventional programmes (fable I); it can be diagnosed preclinically by means of neonatal screening and subsequent specific laboratory tests;,,3-5 and its serious sequelae, including mental retardation, are preventable by early dietary treatment'·· Before the advent of newborn screening programmes for the prevention of PKU, relatively high numbers of patients in centres for the mentally handicapped owed their institutionalisation to this genetic disease.,-g
Genetic Services, Department of National Health and Population Development, Pretoria H. W. Hitzeroth,
M.se. (GENETICSl. DR.RER.NAT. (FREIBURGl. B.SC.
D. C. Brill, B.SC. HONS (MATHS/STATS) Chemical pathology laboratory, Pretoria C. E. Niehaus,
B.SC. (PHARM.). M.B. CIl.B., D.C.f' (LOND.). F.R.C.PATH.
SAMJ
Volllme 85 No. 1 January 1995
Table I. Incidence of PKU in some countries/populations, as relevant for South Africa""'"
Austria Australia Belgium England Ireland
1:8200 1:9000 1:6 000 - 8 100 1:19000 1:4 500 - 7 700
Scotland The Netherlands New Zealand USA (whites) USA (blacks)
1:6000 1:17 000 1:16000 1:14000 1:50000
Comprehensive and effective newborn screening programmes for the prevention of PKU began to be implemented on a state- (Massachusetts, USA) and countrywide scale in the early 1960s. These have in the meantime become accepted generally as part of routine primary health care services in many countries, where this has been recognised as a cost-effective and affordable priority. The impact of such screening programmes over time has been to reduce dramatically the incidence of new cases of PKU in mental institutions, e.g. in the USA and Canada."·11 The white population of South Africa is primarily of western European origin with its well-known, relatively high incidences of PKU (Table I). It was therefore a plausible working hypothesis that PKU should be as common among the descendants of the European immigrants to South Africa, as among their populations of origin. This implied that it would be worthwhile to consider implementing a pilot newborn screening programme for investigating the costeffectiveness and feasibility of more formal and comprehensive screening programmes for the prevention of PKU in South Africa, if found to be warranted. The first PKU screening programme in South Africa was launched in Johannesburg and continued for about 3 years (1964 - 1967) (personal communication - Johannesburg City Health Department, 1989). The test procedure comprised the Phenistix test on urine specimens of babies aged approximately 2 - 3 weeks (first test) and 6 weeks (repeat test). These were performed by health visitors in private homes. In total, about 36 000 babies underwent the first test and about 30 800 both tests; these were performed mostly on white (about 90%), but later also on brown and Asian babies (about 10%). Although some babies were found to be 'positive' or to have an indeterminate result on the screening test, these results were not confirmed on subsequent specific tests. Hence, no PKU baby was diagnosed from this screening programme (and no 'missed' cases were subsequently detected from this cohort of newborns). However, as is well known today, the Phenistix technique is insufficiently sensitive and many positive PKU cases may be 'missed' by this test. The point was also made that the Johannesburg screening programme had not convincingly ascertained the incidence of PKU in South African whites. '2 Against this background it became more important at that time again to address the question of the incidence of PKU in South Africa, and to explore strategies required for its prevention, if found justifiable. For the period 1979 - 1981, Genetic Services of the then Department of Health and Welfare embarked on an exploratory neonatal screening programme, inter alia for the detection of PKU. This was then superseded by a more formal screening programme
Volume 85 No. 1 January 1995
SAMJ
(February 1981 - October 1986). The present communicatiqn presents the results of these screening programmes for the sake of the record, and attempts to establish the most likely incidence of PKU in South African whites. As will be shown, the results do not justify a newborn screening programme for PKU in terms of cost-effectiveness and other competing health priorities in South Africa. A tentative alternative option to newborn screening, Le. appropriate and specialised preventive services for high-risk PKU families (as is the case with many other genetic diseases), is presented for consideration.
Subjects and methods For logistical reasons it was decided to implement the screening programme in the Pretoria area, and to concentrate initially on white babies because of the suspected higher incidence of PKU within this population group (see Discussion). It was endeavoured, as a matter of routine, to include all consecutive (unselected) babies : delivered in the five maternity clinics serving the selected area. As required for PKU (and other feeding-dependent metabolic disorders), the blood specimens were taken at 3 - 5 days of age, by way of heel-prick and blood-spotting on standard filter paper cards. The collection technique, handling, storage and testing procedure complied with the requirements of the adopted methodology. The laboratory assay was usually done within a week of collection, and entailed the standard thin-layer chromatography (TLC) technique for the detection of phenylalanine (for PKU), and other metabolites for the detection of a variety of other amino acidopathies. TLC performed for this purpose and as an equivalent alternative to the Guthrie test was the method of choice at that time," as also used in the screening laboratory at Great Ormond Street Hospital for Sick Children, London (where one of us, CEN., had obtained first-hand laboratory experience). The regulations of the then Department of Health and Welfare (as well as of the subsequent Department of National Health and Population Development) require tender quotations for the laboratory tests, to be done according to accepted specifications. The successive tenders (renewed at intervals of 2 years) were awarded first to one particular private pathology laboratory (for the duration of the exploratory phase: 1979 - 1981) and thereafter to another one (1981 - 1986), both in Pretoria. The major part of the latter, formal phase of the screening programme was conducted under the technical supervision of one of us (CEN.). The sampling and laboratory procedures have also been discussed in greater detail in the context of screening for congenital hypothyroidism. t<
Results During the exploratory phase (1979 - 1981) approximately 14 000 newborns were screened for PKU and other amino acidopathies (as well as congenital hypothyroidism). Within this period 1 case of PKU was diagnosed clinically in
SAMJ ARTICLES
Pretoria. On checking this patient's record it was discovered that she had been tested as a newborn and found negative at the very beginning of the experimental screening phase (September 1979). She therefore represents a false-negative or 'missed' case. 15 During the more formal continuation of the screening programme at the second private pathology laboratory (1981 - 1986), another 45 600 newborns were screened and no cases of PKU were found. Private paediatricians in Pretoria, as well as the Department of Paediatrics of the University of Pretoria, were generally aware of the screening programme. It was expected that any 'missed' cases would come to the attention of their respective practices/clinics, as had been the case during the exploratory phase. '5 However, no further 'missed' cases of PKU came to our attention during the subsequent years. Of the other amino acidopathies screened for, only 1 case of tyrosinaemia was found among the cohort of 45 600 newborns.
Discussion From the results as presented it follows that 1 PKU case was born from among some 14 000 newborns (experimental phase) and none was found among the 45 600 subsequent newborns of the second phase. On statistical analysis using the Poisson distribution, it follows that a combined incidence of 1 PKU case found in 59 600 newborns is compatible (within the 95% confidence interval) with a 'true' incidence of not more than 3 such cases from among that number of newborns. From the screening experience evaluated here, the tentative conclusion is that the incidence of PKU in the Pretoria area (and possibly among South African whites in general) seems to be considerably less than in their European populations of origin. The incidence of PKU in South African blacks, browns and Indians has yet to be determined. Screening data on black and Indian populations in other countries,·,6 show PKU to be considerably less common in these racial groups than among whites. From local clinical experience, tentative observations (informal personal communications) suggest that while white PKU patients are occasionally seen, only 1 black patient has been diagnosed in this country.17 Whereas biochemical screening surveys of inmates of institutions for the mentally handicapped in western Europe and North America before the advent of newborn screening and prevention showed PKU to be the most common of such metabolic disorders (1 - 3% of all institutionalised patients?·9), the equivalent incidences for this country are far lower. Biochemical screening surveys at two large and representative South African Care and Rehabilitation Centres for white patients gave the following results: (I) PotchefstroomlWitrand: 1 568 patients screened, 1,29% found to have a metabolic disorder and 0,13% (2 patients) PKU;,B.,9 (iJ) Cape Town/Alexandra: 1 087 patients screened, 0,6% found to have a metabolic disorder and 0,28% (3 patients) PKU!O A similar screening programme at the Rand West (Millsite) institution for mentally retarded black patients showed that
of 267 patients screened, none had PKU and only 1 had a detectable metabolic disorder. 21 The tentative clinical observations, as well as the data from mental institutions summarised above, support the conclusion drawn from the results of the newborn screening programmes presented here. PKU seems much less common among whites than elsewhere, and particularly rare among blacks, browns and Indians of this country (Table I). Given the above conclusion it was decided that screening for PKU for any population group in South Africa was neither cost-effective nor justifiable, especially against a background of other, more pressing health priorities. The newborn screening programme for PKU and other amino acidopathies was duly discontinued in 1986 and no such programme is currently being conducted in South Africa (as far as we know). Over recent years as many as 20 PKU families, each with one or more affected children of different ages, have been identified by anecdotal case finding (Genetic Services unpublished data). These represent high-risk families with a known recurrence risk for PKU of 1 in 4. Such case-finding and identification of at-risk families (as routinely done for many other genetic diseases) provides opportunities for the prevention of recurrences. This conventional strategy is therefore an alternative option for identification of PKU in South Africa in the absence of routine newborn screening. The objective is to make appropriate information and comprehensive genetic services, such as the following, directly available to the families concerned, for their voluntary utilisation: (I) ongoing clinical evaluations, genetic counselling and dietary guidance for all affected (including pregnant) PKU patients and their families; VI) the option of having molecular-genetic investigations done for the diagnosis of the underlying genetic defect and for the detection of heterozygous carriers in as many family members as would wish to avail themselves of this option;" (iil) voluntary carrier tests on (would-be) spouses of identified PKU heterozygotes; (iv) the option of a prenatal test for the diagnosis of an affected fetus in high-risk PKU pregnancies; (v) the offer to have newborn screening tests done on all babies born to these (extended) families; and (vi) guidelines for the dietary treatment of an affected baby (as identified by the abovementioned individual newborn screening test). The comprehenSive, preventive genetic service as outlined above is in keeping with what is being offered for many other genetic diseases worldwide. PKU in South Africa therefore reverts to the status of such a 'conventional' genetic disease. It is suggested that the recommerided approach provides an appropriately effective alternative option for the prevention of PKU (given the local circumstances and the present level of laboratory expertise), in the absence of any large-scale newborn screening programme in South Africa. The authors would like to thank Professor 1. Jenkins (Department of Human Genetics, SAIMR, Johannesburg) for his comments on the manuscript.
SAMJ Volume 85 No. I January /995
REFERENCES 1. Levy HL. Genetic screening. Adv Hum Genet 1973; 4: 1-104. 2. Guttler F. Phenylketonuria: 50 years since Foiling's discovery and still expanding our clinical and biochemical knowledge. Acta Pediatr Scand 1984; 73: 705-716. 3. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 1963; 32: 338-343. 4. Efren ML, Young 0, Maser HW. MacCready RA. A simple chromatographic screening test for the detection of disorders of amino acid metabolism. A technique using whole blood or urine collected on filter paper. N Engl J Med 1964;
270: 1378-1383. 5. Scriver CA, Clow CL, Lamm P. On the screening diagnosis and investigation of hereditary amino-acidopathies. Clin Biochem 1973; 6: 142-188. 6. Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet 1953; 2: 812-813. 7. Carson NAJ, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 1962; 37: 505-513. 8. Moore PT, Martin MC, Coffey VP. Screening for biochemical abnormalities in the urine of the mentally handicapped in Dublin. J Ment Defic Res 1972; 16: 128-138. 9. Thoene J, Higgins J, Krieger I, Schmickel R, Weiss L. Genetic screening for mental retardation in Michigan. Am J Ment Defic 1981; 85: 335-340. 10. Webb JF, Khazen RS, Hanley WB, Partington MW, Percy WJA, Aathbone JC. PKU screening - is it worth it? Can Med Assoc J 1973; 108: 328-329. 11. MacCready AA Admissions of phenylketonuric patients to residential institutions before and after screening programmes of the newborn infant. J Pediatr 1974; 85:
383-385. 12. Jenkins T. The role of screening in the prevention of inherited disease in South Africa. S Air Med J 1977; 51: 832-837. 13. Ersser AS, Smith I, Seakins JWT. Amino acids and related compounds. In: Smith I, Seakins JWT, eds. Chromatographic and Electrophoretic Techniques Vol 1. 4th ed. London: William Heinemann Medical. 1976: 75-121. 14. Bernstein AE, Op't Hof J, Hitzeroth HW. Neonatal screening for congenital hypothyroidism. A decade's review, including South Africa. S Afr Med J 1988; 73:
339-343. 15. Potze F. Gevalbespreking: Fenielketonurie. Geneeskunde 1982; Feb: 91-97. 16. Hofman KJ, Steele G, Kazazian HH, Valle D. Phenylketonuria in US blacks: molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet 1991 ;
48: 791-798. 17. Kruger N, Annandale S, Cann N, et al. A black family with hyperphenylalaninemia. Proceedings of the 4th National Congress of the Southern African Society of Human Genetics. Vereeniging, 25-28 March, 1991. 18. Reinecke CJ, Mienie LJ. Some inborn errors of metabolism at a local institute for mentally retarded patients. J Inherited Metab Dis 1981; 4: 119-120. 19. Reinecke CJ, Mienie LJ, Hitzeroth HW, Cp't Hof J. Screening for inborn errors of metabolism among mentally retarded patients. S Afr Med J 1983; 63: 14-16. 20. Henderson HE, Goodman A, Schram J, Diamond E, Daneel A. Biochemical screening for inherited metabolic disorders in the mentally retarded. S Afr Med J
1981; 60: 731-733. 21. Op't Hof J, Glynn J, JackJin L, et al. A multidisciplinary diagnostic/genetic study on 267 non-caucasian patients with severe mental retardation of the Millsite Care and Rehabilitation Centre. Quoted in: Screening for metabolic disorders. Colloquium on Inborn Errors of Metabolism. MRC (South Africa)/National Science Council (Republic of China), Mabula Lodge, October 1989. 22. De Wet WJ, Mbhr I, Op't Hof J. Haplotype analysis of the PAH gene in South African families with PKU. Proceedings of the 3rd National Congress of the Southern African Society of Human Genetics, Durban, 30 August - 1 September 1989. 23. Collaborative Study (Review). Frequency of inborn errors of metabolism, especially PKU, in some representative newborn screening centers around the world. Humangenetik 1975; 30: 273-286.
Accepted 13 Dec 1993.
Micromanipulation at an infertility centre A. D. Esterhuizen,
c. A. Groenewald,
H. W. Lindeque,
M. V. K. Giesteira, G. P. J. Labuschagne Aim. Human in vitro fertilisation (IVF) and gamete intrafallopian transfer have been used in the management of various forms of infertility. In cases of severe male-factor infertility, fertilisation can be a factor. In this study micromanipulation was used to increase fertilisation in such cases. Methods. Two micromanipulation techniques, subzonal sperm injection (SUZI) and partial zona dissection (PZD), were used to assist fertilisation in patients with abnorTl)al semen parameters. Ten couples with severe oligo-, teratoand asthenozoospermia participated in the SUZI programme. Seventy-three oocytes were obtained from these 10 patients. PZD was used on day 1 oocytes in cases of male infertility as well as a rescue attempt on day 2 oocytes when fertilisation had failed after routine insemination. Results. The SUZI technique had a fertilisation rate of 37,7%. In this group, a biochemical pregnancy was achieved. Differences between the fertilisation rate of conventionallVF (33,3%) and PZD (56,3%) in cases of male infertility, were not statistically significant although a clinical difference could be detected. PZD was statistically effective in facilitating fertilisation (37,5% v. 8,3%) in couples where this procedure was introduced to reinseminate 24-hour-old unfertilised oocytes. Four patients received PZD reinseminated embryos. An average of 1,45 PZD embryos were replaced and 1 implantation pregnancy was confirmed. Conclusion. The micromanipulation results are encouraging arid seemed to increase the efficiency of IVF in humans. Furthermore, our data support the conclusion that micromanipulation procedures can bring about pregnancies. S Afr Med J 1995; 85: 36-40.
I n vitro fertilisation (IVF) is effective in the management of a variety of infertility problems. However, many cases of male
Garden City Reproductive Biology Unit, Johannesburg
A. D. Esterhuizen, M.SC. C. A. Groenewald, M.B. CH.B., M.MED. (0.
& G.), M.C.O.G. (SA)
H. W. Lindeque, M.B. CH. B., M.MED. (0. & G.), FC.O.G. (SA) M. V. K. Giesteira, M.B. CH.B., M.MED. (0.
& G.), M.C.O.G. (SA.), FC.O.G. (SA), M.R.C.O.G.
(LOND.)
G. P. J. Labuschagne, M.B. CH.B.,
Volume 85 No. 1 January 1995
SAMJ
M.MED. (0. & G.), M.C.O.G. (SA), FC.O.G.