PRINCIPLES OF BIOCHEMICAL SCREENING & COMMUNICATING RISK TO THE PARENTS
Howard Cuckle & Indera Sehmi (UK)

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Maternal age screening for Down's syndrome is ineffective. Despite the eight-fold increase in the risk of Down's syndrome between age 30 and 40, most cases occur in young women because most pregnancies are in women aged under 30.

Current best screening practice for Down's Syndrome involves the use of multiple maternal serum markers, tested in the second trimester. Most programmes use a combination of human chorionic gonadotrophin (hCG) or free b-hCG with or without unconjugated estriol (uE3). The standard approach is to combine information on the maternal age and the marker profile to estimate each woman's risk of giving birth to a baby with Down's Syndrome. Statistical modelling predicts that:

1. Combinations using free b-hCG are more effective than those using hCG
2. Use of uE3 increases the detection rate
3. For a 5% recall rate a detection rate of 67% can be achieved. These predictions have been confirmed by the 21 large prospective intervention studies that have been published so far.

The prospective studies also provide other important information. Firstly, they demonstrate the acceptability of screening: overall there was an 80% uptake rate and of those with positive results 79% accepted invasive prenatal diagnosis. Secondly, they not only show that the models can predict detection rates but that screening programmes correctly estimate risks for individual women.

These are reassuring results and statistical models can now be confidently used to predict improved screening policies. In particular there is the possibility of using a fourth second trimester marker, inhibin A. Eleven studies have reported that the level of maternal serum inhibin-A is raised on average in second trimester pregnancies with Down's Syndrome. When all of them are combined in a meta-analysis, the median value in 570 Down's Syndrome pregnancies is 1.84 MoM and modelling predicts that measuring inhibin-A as an additional marker will increase the detection rate by about 7%.

Several markers of Down's Syndrome have been discovered in maternal urine. The b-core fragment is the major metabolic product of hCG in maternal urine and second trimester levels are increased on average in Down's Syndrome pregnancies to a greater extent than maternal serum hCG and free b-hCG. The cumulative result from a total of 253 cases in 8 series is a median of 3.75 MoM (compared with 2.02 and 2.30 for hCG and free b-hCG). However, the standard deviation (SD) of the urine marker is very wide, partly because only a random urine sample is available, and as a result it is no more effective than the serum markers. There is significant heterogeneity between the studies and it is possible that a better assay will eventually emerge with an acceptable SD.

At present, most centres screen for Down's Syndrome at 15-19 weeks gestation so that the same sample can be used in alpha-fetoprotein (AFP) screening for neural tube defects (NTDs). Moving the test to earlier in a pregnancy has obvious advantages: earlier reassurance and if a therapeutic abortion is necessary it could be completed before foetal movements are felt and less traumatically. The only disadvantage of earlier screening is that NTD detection would require either a separate AFP test after 15 weeks (it is invalid earlier) or reliance on an ultrasound anomaly scan at 18-20 weeks.

Three of the established second trimester markers are of value in the first trimester, namely free b-hCG, AFP and uE3; in the first trimester fCG is a much poorer marker than free b-hCG. In addition another placental product, pregnancy associated plasma protein A (PAPP-A), has consistently yielded reduced levels on average in first trimester Down's Syndrome pregnancies, although the reduction is greatest in the early first trimester.

Several second trimester ultrasound markers of Down's Syndrome have been reported but they are ineffective. In contrast ultrasound nuchal translucency (NT) is a highly predictive first trimester marker. Early studies reported the NT in m rather than in gestation standardised terms resulting in lack of comparability between centres. This has now been overcome with more recent studies expressing results in MoM's. The most reliable information on the average NT in affected pregnancies is from the massive multi-centre prospective intervention study organised by the Foetal Medicine Foundation. Unlike the other studies it is based on routine scanning among low risk women in non-specialist units. Among the first 326 Down's Syndrome pregnancies in the study the median NT was 2.27 MoM, or in potentially viable foetuses 2.02 MoM.

Statistical models predict that the detection rate of a 5% recall rate, using a combination of PAPP-A and free b-hCG at 9-11 weeks, is similar to that of 2-3 marker second trimester screening. The addition of further serum markers yields a further increase in detection comparable with adding inhibin A in the second trimester. NT alone had a predicted detection rate of a same magnitude. But by far the best results are predicted for the combination of serum markers and NT where the detection rate for a 5% recall rate is 88%.

No prospective intervention studies have yet been published for screening in the first trimester with the serum markers. But the results of NT screening among almost 100,000 pregnancies in the Foetal Medicine Foundation study has been reported. The recall rate was 8% and the observed detection rate was 82%, which is equivalent to 78% in potentially viable foetuses, similar to the rate of 77% predicted for an 8% recall rate using models.

There have been considerable technical advances in recent years. However, the methods of helping patients reach an informed choice have not progressed. Screeners need to develop new information and decision aids. Videotapes, the internet and telephone helplines could all be used to reinforce the more conventional leaflets and face-to-face interviews. Whatever method is used it is essential that the information includes:

1. the natural history of Down's Syndrome
2. the maternal age-specific risk of the disorder
3. serum markers
4. how the age and marker information is combined to produce a final risk
5. how factors such as gestational error and maternal weight can alter the risk
6. how results are classified as 'positive' or 'negative'
7. the fact that most pregnancies with positive results will not result in a baby with Down's Syndrome
8. that some with negative results will in fact be affected, and
9. amniocentesis and its hazards.

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