Authors' objectives:

To summarise the expected performance of serum and ultrasound makers for Down's syndrome.

To evaluate the effectiveness, safety and cost-effectiveness of the different methods of antenatal screening and diagnosis.

To review current screening practice for Down's syndrome.

To specify the most appropriate method of Down's syndrome screening and identify areas for further research.

Authors' results and conclusions: Principles of antenatal screening for Down's syndrome Methods of screening need to be fully evaluated before being introduced into routine clinical practice. This includes choosing markers for which there is sufficient scientific evidence of efficacy, quantifyingperformance and establishing methods of monitoring performance. Screening services need to be well integrated and managed. Serum markers at 15-22 weeks of pregnancy Screening performance varies according to the choice of markers used and whether ultrasound is used to estimate gestational age. When the latter is used in combination with maternal age, the detection rate for a 5% positive rate is estimated to be 59% for the double test (AFP and hCG), 69% for the triple test (AFP, hCG, uE3) and 76% for the quadruple test (AFP, hCG, uE3, inhibin A). Urinary markers and foetal cells in maternal blood Urinary beta-core hCG has been shown to be raised in Down's syndrome pregnancies. Urinary total oestriol and free beta-hCG may also be of value but it would be premature to introduce them into screening practice. Foetal cells can be identified in maternal circulation and techniques such as fluorescent in situ hybridisation can be used to identify Down's syndrome. However, this does not have the performance, simplicity or economy needed to replace existing methods. Demonstration projects Several demonstration projects using triple and double tests have been conducted, in which screening uptake was about 80% with screen positive rates of about 5-6%. Approximately 80% of women with positive results had an invasive diagnostic test, and about 90% of those found to have a pregnancy with Down's syndrome chose to have a termination. Ultrasound markers at 15-22 weeks of pregnancy There are a number of ultrasound markers of Down's syndrome at 15-22 weeks, of which nuchal fold thickness is the most discriminatory on its own, but not discriminatory enough for screening. The markers could be used in combination with the serum markers but no studies assessing this have been completed to date. Serum and ultrasound screening at 10-14 weeks of pregnancy The serum markers pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG, combined with maternal age have an estimated detection rate of 62% for a 5% false-positive rate. Nuchal translucency is a useful marker of Down's syndrome. There are differing estimates of screening performance and some are subject to bias. Further studies are needed to quantify the performance of this test alone and in combination with biochemical markers. There is also a need to compare the performance of such screening with screening at 15-22 weeks to determine which has the greater efficacy and which is the most cost-effective. Methods of antenatal diagnosis The standard method of antenatal diagnosis is amniocentesis at about 15 weeks of pregnancy followed by karyotyping of cultured cells from the amniotic fluid. The excess foetal loss attributed to amniocentesis is approximately 0.9%. Before 15 weeks of pregnancy, transabdominal chorionic villus sampling (CVS), although less accurate than mid-trimester amniocentesis, seems to be the diagnostic method of choice. Cost-effectiveness of serum screening In general, serum screening is more cost-effective than screening based on maternal age alone at detection rates of about 50% or greater. As the number of screening markers increases, the cost per pregnancy increases but, if an extra marker is sufficiently discriminatory, the cost per Down's syndrome birth avoided may decline. For example, the estimated cost per pregnancy screened and the cost per Down's syndrome birth avoided is 8.90 GBP and 25,600 GBP for the double test; 9.60 GBP and 22,600 GBP for the triple test, and 11.60 GBP and 23,100 GBP for the quadruple test. Safety Screening leads to women having an invasive diagnostic procedure that can result in foetal loss. As screening performance improves, the number of unaffected foetal losses per Down's syndrome birth avoided declines by 24%, from 0.59 (double test) to 0.45 (quadruple test). Psychosocial aspects Several studies have shown that the anxiety associated with screening is short lived and can be minimised by the provision of clear and simple information before screening, together with counselling for women with positive results. Health professionals often do not have adequate knowledge of serum screening and therefore have difficulty in reporting screening results to women. Quality assurance and monitoring Quality assurance and monitoring should be an integral part of a screening service. It is currently not possible to tell whether screening centres undertake epidemiological monitoring and service audit satisfactorily. Current screening practice Serum screening for Down's syndrome has been widely introduced into practice and has enabled a substantially higher proportion of pregnancies to be identified without materially increasing the proportion of women requiring an invasive diagnostic procedure. Although the screening approach, using multiple markers concurrently, was novel, it has been introduced reasonably effectively using statistical methodology that has been accepted and empirically validated. There is also an active research programme being conducted alongside the clinical services. In spite of the achievements, a number of problems were identified - incomplete coverage of screening, inconsistent practice and a lack of overall direction. The introduction of alternative methods of screening has led to multiple stepwise screening in an uncoordinated manner which is confusing to staff and patients. Some research findings have been introduced into practice before being fully evaluated.

Authors' recommendations: The evidence indicates that screening using the triple test with maternal age is more effective, safe and cost-effective than the double test. The performance of the quadruple test including inhibin A appears somewhat better. There is substantial variation in screening services for Down's syndrome throughout the UK. This needs to be rectified. The authors recommend that policy makers should ensure overall direction, with a written policy, specified funding and line responsibility, while preserving local commitment. The authors suggest the establishment of local screening units (covering 15,000 births per year - about three to four maternity units) which would have full responsibility for their service. These would each have a dedicated screening coordinator who would work together with a screening consultant. Inequity of access to the service and the current multiple stepwise uncoordinated screening of Down's syndrome should be addressed. The tendency to offer more than one method of screening to the same women at different stages of pregnancy should be avoided. There is evidence that better staff education and training is needed so that patients are adequately informed about screening and its implications.

Authors' methods: Review.

Project Status: Completed

URL for project: http://www.hta.ac.uk/908

Year Published: 1998

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: England, United Kingdom

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk

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