Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...

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Assessment of screening potentialacceptability of invasive prenatal diagnosis in womenfound to be carriers, and the consequent terminationof pregnancy, would probably be similar tothat found in cascade screening and other studiesof prenatal diagnosis. Hence, about three-quartersof these women would take up prenatal diagnosis(see chapter 9), and nearly all the affected male andhalf the affected female foetuses would be terminated(see Table 10). Thus, if antenatal screening forfragile X syndrome were shown to be acceptable topregnant women, its effectiveness in reducing birthprevalence might be comparable with screening forDown’s syndrome.The feasibility of cascade screening for fragile Xsyndrome rests on the practical experience of thefour studies in which it has been attempted (seepage 33). The most informative study in termsof effectiveness is that from New South Wales.Within the affected families known to the screeningprogramme, there has been a dramatic reductionin affected births both through avoidanceof future pregnancies and through prenataldiagnosis (Robinson et al, 1996). However, thereis no reliable information on the impact of thisscreening on the total population birth prevalenceof fragile X syndrome.Pre-conceptual screeningInsofar as the next step to pre-conceptualscreening is prenatal diagnosis, the same detectionrate, false-positive and predictive values will apply.Some women may avoid further pregnancies as aresult of screening. Strictly, those who would nothave had an affected foetus if they had conceivedconstitute additional false-positives but it wouldbe impractical to take account of this.Effectiveness cannot be estimated at present,although the effect of a positive result on futurereproduction is likely to be similar to that seen withcascade screening. In the absence of pilot studies,it is difficult to judge how feasible and acceptablepre-conceptual screening for fragile X syndromewould be. If the experience with cystic fibrosis(Brock, 1994) is true for all genetic diseases thenantenatal screening is likely to be much moreeffective than pre-conceptual screening.Cascade screeningThe detection rate and negative predictive value ofcascade screening will be similar to pre-conceptualscreening but the other parameters will differbecause the target population are selected becauseof high prior risk. Therefore the positive rate ishigh and, although a large proportion of the PMswill expand, the false-positive rate must be greaterthan in the general population. The positive predictivevalue will be higher too, primarily becauseof the greater prior risk.Paediatric screeningWith paediatric screening, the child is the affectedindividual and a test for the FM will also have anapproximately 100% detection rate and negativepredictive value. The test will only yield a falsepositiveresult if a female has an FM but does nothave fragile X syndrome. Thus, false-positives willbe rare and, assuming that an equal number ofmales and females are tested, the positivepredictive value will be 3 in 4.There is practical experience of paediatric screeningbut its effect on prognosis is unknown. Thereare medical, educational, psychological and socialinterventions which are believed to improve symptoms(see page 6). However, there are no clinicaltrials or other comparable data that can be usedto confirm that early treatment leads to improvedlong-term benefit compared with treatment appliedat the usual time of presentation. Common sensedictates that some benefits will accrue but theyneed to be quantified.Neonatal screeningThe screening performance parameters willbe similar to paediatric screening. There is nopractical experience of this kind of screeningfor fragile X syndrome and, as with paediatricscreening, there is the same problem ofproving effectiveness.44
Health Technology Assessment 1997; Vol. 1: No. 4Chapter 12Human and financial costs of screeningHazards of prenatal diagnosisAmniocentesisThe principal hazard of amniocentesis is miscarriagebut the excess risk associated with the procedureis difficult to quantify precisely. Some 3–4%of mid-trimester pregnancies will miscarry withoutamniocentesis and, in a particular case of foetalloss following the procedure, it is only rarely possibleto directly attribute the adverse outcome tothe procedure. Cases of amnionitis or chronicamniotic fluid leakage would be attributable butthese are relatively rare consequences. Studies ofwomen having amniocentesis and matched controlsare biased. When amniocentesis was a newprocedure, it was more available to women ofhigher social class with a lower miscarriage rate,so early studies were biased towards the safety ofthe procedure. Later, when the main indicationswere advanced age and abnormal biochemistryor ultrasound, factors associated with increasedrisk of miscarriage, the bias went the other way.There has been only one randomised trial ofamniocentesis (Tabor et al, 1986). The foetalloss rate in more than 2000 women randomisedto the procedure was 0.8% higher than in thecontrol group. While this is necessarily limitedto the skills and experience of a single obstetricunit, the results provide the only unbiasedestimate of hazard. Thus the excess miscarriagerate is usually quoted as between 0.5% and 1%.Chorionic villus samplingFive major comparative studies have shownthat, when performed at 9–12 weeks by a skilledoperator, CVS has a comparable foetal lossrate to amniocentesis (Canadian CollaborativeCVS–Amniocentesis Clinical Trial Group, 1989;Rhoads et al, 1989; MRC Working Party on theEvaluation of Chorionic Villus Sampling, 1991;Smidt-Jensen et al, 1992; Ammala et al, 1993).The possibility of another important consequenceof the procedure has been raised, namely thecausation of limb reduction defects in the foetus.An international registry of CVS organised bythe World Health Organization has been monitoringthe procedure, so that any iatrogenic effectswill not go unnoticed. The latest reported resultsbased on 138,000 infants found no excess oflimb reduction defects compared with data onthe background prevalence of these conditions(Froster & Jackson, 1996).Peripheral umbilical cordblood samplingThe sampling of blood from the umbilical cordwould appear to be more hazardous than bothamniocentesis or CVS. However, there is no evidencethat it results in more foetal losses thanthe other procedures. There have been norandomised trials but a meta-analysis has beenperformed on six series, each including more than100 cases (Ghidini et al, 1993). Patients withfoetal pathological conditions were excluded,because a compromised foetus is often theindication for carrying out PUBS. The miscarriagerate in the remainder was only 1.4%,which is reassuringly low. There are othercomplications but they are not major.Psychological burdenScreening for fragile X syndrome in commonwith other screening programmes will generateanxiety. First, for many the offer of screeningitself will raise the possibility of a congenitalabnormality not previously considered. Second,there is likely to be extreme anxiety in thosefound to have an FMR-1 mutation. In some casesthere will be,in addition, the negative psychologicaleffects of terminating a previously wantedpregnancy, or the possibility of stigma in thoseborn despite screening. Although many of theseproblems are a necessary consequence of screening,they can be ameliorated by high qualityinformation being given at all stages of thescreening process, and by genetic counsellingwhen appropriate.Information givingA particular problem with genetic screening isthat complex information needs to be given tothose offered the test. This concerns clinicaleffects, patterns of inheritance, laboratory tests,and calculations of risk. With fragile X syndromethere is the particular problem of explaining thatthe prognosis of an individual female with an FMcannot be predicted from the DNA test. Those45
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