When the new test is compared to combined first trimester screening purely on sensitivity and specificity results, non-invasive prenatal testing appears to be better.20 Combined first trimester screening does, however, provide other information. Ultrasound screening allows accurate dating of the pregnancy, recognition of structural (rather than chromosomal) anomalies and identification of multiple pregnancies. It may also identify pregnancies at risk of other adverse obstetric outcomes such as pre-eclampsia and fetal growth restriction.
At present, most national and international guidelines suggest that non-invasive prenatal testing should be restricted to women with a high risk of an affected pregnancy.21-23 Although it is highly specific, the prevalence of a Down syndrome pregnancy is low in women who have not had previous screening or who are considered to have a low risk after prenatal screening. The positive predictive value (proportion of positive results that are true positives) in an unselected population is at best 50%. In other words, one in two positive test results in low-risk women are likely to be false positives – and test results need to be confirmed by amniocentesis before any intervention.
If non-invasive prenatal testing is restricted to patients who have previously been screened for Down syndrome and found to have a high risk, then a positive result will imply that the fetus is indeed affected, and a negative result will imply the fetus is unlikely to be affected. False positive results have been reported and all positive results should be confirmed by amniocentesis. Using quantitative fluorescent polymerase chain reaction, the result can be confirmed within 24 hours. If women have not had any previous screening or are considered to be low risk after prenatal screening, confirmation of a positive result will be more important.
One attraction of this test is that the sample is very stable so it can be transported long distances to a centralised facility. Combined first trimester screening relies on the ability to provide high quality obstetric ultrasound facilities locally. Non-invasive prenatal screening may help to reduce the inequality of access in rural areas.24 However, at present the test is not reimbursed on the Medicare Benefits Schedule and may cost a patient over $500.
Options for screening strategies
As non-invasive prenatal testing is so sensitive, one option is to offer this test to women who have had a high-risk result from combined first trimester screening. It has been suggested that this may lead to 80% reduction in the current invasive testing rate. While this will improve the overall specificity of the screening strategy, it does not take advantage of the high sensitivity of non-invasive prenatal testing for the population as a whole.
An alternative strategy is to offer all women noninvasive prenatal testing and an ultrasound scan. However, this will increase the cost of the screening program quite significantly.
A third strategy would be to change the reporting strategy of combined first trimester screening to identify three groups:
- a high-risk group (>1 in 50) offered invasive testing
- a low-risk group (<1 in 1000) reassured and advised no further screening is necessary
- an intermediate-risk group (1 in 50 to 1 in 1000) who would be advised about the availability of, and offered, non-invasive prenatal testing.
This is described as a contingent screening model with the use of the test being contingent on the results of combined first trimester screening. The advantage of this strategy would be an overall increase in detection of trisomy 21 (97% sensitivity) with a reduction in the false positive rate (<1.5%). This model is outlined in more detail in Fig. 2.
When combined first trimester screening is not possible
Sometimes combined first trimester screening is not available, for example for those living in remote areas or presenting at more than 14 weeks gestation. In these circumstances non-invasive prenatal testing could be used, but only after an ultrasound scan to check that the pregnancy is viable and that the placenta has a normal appearance.