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Risk and Down's screening

Study
Results
Comment

Screening for Down's syndrome with four measurements in maternal serum is increasingly common. The four markers are alphafetoprotein, unconjugated oestriol, human chorionic gonadotrophin and inhibin-A. Results are used by a computer programme, together with gestational age, to compute a risk of an affected child. A positive test is one in which the risk of an affected child is higher than 1 in 300. We now know how this worked in practice in nearly 50,000 women over five years [1].

Study


The population were 46,193 pregnancies in 14 London hospitals over five years, in which the quadruple test was applied to serum samples between 14-22 weeks of pregnancy. A test was deemed positive if the computed risk of an affected foetus was 1 in 300 or greater (where greater risk means lower numerical values, 1 in 200, 1 in 100 etc). Gestational age was determined by ultrasound in 4 of 5 women.

Results


There were 88 affected pregnancies, giving an overall risk in this population of 1 in 525, not taking age into account. With the quadruple test there were 3,271 positive tests that detected 71 affected foetuses. Just under 98% of all positive tests were false positives. Sensitivity, specificity and likelihood ratios are shown in Table 1. The chance of an affected foetus following a positive test was 1 in 46, and with a negative test was 1 in 2525.

Table 1: Results of Down's syndrome screening using the quadruple test and maternal age

 

 

Likelihood ratio

Chance of an affected foetus with test

Scenario

Sensitivity

Specificity

Positive

Negative

Positive

Negative

Quadruple test 0.81 0.93 11.6 0.21 1 in 46 1 in 2525
Maternal age 35 or older 0.51 0.79 2.5 0.62 1 in 148 1 in 850
Outcomes predicted from a cohort of 46,193 women tested over 5 years at London hospitals. The risk of an affected foetus overall was 1 in 525.

By comparison, maternal age alone, using 35 years or older as a cut off, would have detected 45 affected foetuses had 6,659 women proceeded to amniocentesis. The chance of an affected foetus using age over 35 alone was 1 in 148, but was 1 in 850 with a negative test.

Comment


This paper also has information on the use of triple and double tests (where inhibin-A, and inhibin-A and unconjugated oestriol were not included, respectively), but that information was not amenable to similar calculations. The paper also tells us that the uptake of amniocentesis rose with increasing risk, from 43% of women with risks between 1 in 250 to 1 in 300, to 74% in those with risks higher than 1 in 50.

Of women who tested positive and had an affected pregnancy, 62 of 71 had amniocentesis, and 59 of the 62 had a termination. Twenty children were born with Down's syndrome.

Natural frequencies for the quadruple test and maternal age are shown in Figure 1.

Figure 1: Screening for Down's syndrome using natural frequencies for the quadruple test and maternal age



To calculate the chance of an affected foetus with a positive test, the 71 actual cases detected are divided into the sum of all positive tests, in the case of the quadruple test:

(3,200 + 71)/71 = 46 (1 chance in 46)

To calculate the chance of an affected foetus with a negative test, the 17 cases not detected are divided into the sum of all negative tests, in the case of the quadruple test:

(42,905 + 17)/17= 2525(1 chance in 2525)

References:

  1. NJ Wald et al. Antenatal screening for Down's syndrome with the quadruple test. Lancet 2003 361: 835-836.

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