Detecting Down syndrome with genomics

A major US study has shown that non-invasive prenatal testing performs better than invasive methods, but what about the UK?

Fetal anomaly screening is an important part of pregnancy care in the UK for more than 800,000 women every year.

Current approaches combine serum testing and ultrasound scanning in the first and second trimesters of pregnancy to identify various potential fetal abnormalities. These may be primarily physical problems, such as cleft palate or spina bifida, or genetic, whether small-scale gene mutations or large-scale chromosomal aberrations. Serum screening (testing maternal blood samples for levels of selected protein biomarkers) can indicate where there is an increased risk of genetic abnormality in the fetus that may not be otherwise apparent.

Screening for Down syndrome

The most common form of chromosomal abnormality is Down syndrome (trisomy 21), which arises when the fetus has three copies of chromosome 21 instead of the normal two.

The screening programme identifies women at high risk of having a baby with Down syndrome by combining information on age (increasing maternal age is the single greatest risk factor), ultrasound measurements and serum testing results. These women are then offered invasive procedures to sample fetal DNA from the placenta or amniotic fluid for a definitive genetic diagnosis.

Unfortunately, invasive testing carries a small but significant risk of miscarriage of around 1%. Inevitably, this means that some women opt against it (and have to continue pregnancy unsure of whether or not their baby is affected), and others opt to be tested but then lose the baby, including ones who did not in fact have Down’s or any other chromosomal disorder.

Decoding cell-free fetal DNA

Recent advances in non-invasive prenatal testing (NIPT) could have a big impact on this situation. A relatively new technique that selectively detects and copies small amounts of cell-free fetal DNA, which is present in the mother’s blood from early in pregnancy, can permit non-invasive diagnostic analysis. Originally developed for certain rare inherited diseases, NIPT can now identify chromosomal abnormalities including Down’s, with private testing services already available.

Research has shown that NIPT is more effective than standard screening for identifying Down’s in high-risk groups (eg women over 35 or with a previous affected pregnancy). The big question, however, is how well it performs in the normal pregnant population.

Results from a huge new study of more than 15,000 pregnant women in the US have shown that NIPT performs significantly better than normal serum and ultrasound screening in identifying Down syndrome. As well as being more sensitive – correctly identifying all the true cases of Down’s – the NIPT also resulted in far fewer ‘false positive’ results than standard screening; just 0.06%, compared with 5.4%.The upshot of this is that fewer invasive procedures are needed to check suspected cases of Down syndrome, and fewer babies are lost: good news all round.

NIPT in the UK

So will the UK screening programme embrace NIPT? Mass introduction of new technologies is not quite that simple. There are some technical complexities – for example, testing performs less well in obese women.

However, a current UK trial is evaluating how well it could work in the normal antenatal care pathway including a health economic appraisal. Depending on findings, NHS maternity care could soon benefit from this exciting genomic technology.