The impact of free fetal DNA on
ultrasound departments and the NHS Michelle Kemp, Richard Smith
Screening for Down’s syndrome has been continually evolving since it first started in the 1960s. The latest development using free fetal DNA (ffDNA) is set to revolutionise the United Kingdom screening system when it finally becomes integrated into the National Health Service (NHS). However, ffDNA technology is not cheap and has its own challenges, which will need to be tackled before implementing new screening tests into a system which is well established.
C
urrently in the UK, the gold standard for Down’s syndrome screening is the combined test. This is performed between 11+2 and 14+1 weeks of gestation and includes the nuchal thickness measurement, maternal age and serum blood tests for beta human chorionic gonadotropin (hCG)
and pregnancy associated plasma protein A (PAPP-A). Introduction of the combined test has put ultrasound departments under increasing pressure to perform scans which take longer than a simple dating scan, and have to be performed within a narrower window. However, it can give a detection rate of 90% with a false positive rate of 3%1
different. Invasive diagnostic testing is therefore offered for each fetus, if either has a risk of Down’s higher than 1 in 150 using combined screening. Currently 85% of women in the UK are offered first trimester screening and 15% book later and are therefore offered second trimester screening3
. Uptake by those eligible for the screening is about 69%3
About 80-90% of women with a high risk result opt for CVS or amniocentesis, and of those who have a positive result, 92% choose to end the pregnancy3
.
ffDNA technology It has been known for over 50 years that fetal cells can be found in maternal blood, but learning how to exploit that knowledge and isolate fetal DNA from maternal serum to aid diagnosis, is a much more recent discovery. ffDNA can be detected from seven weeks’ gestation and is found at diagnostic levels from eight weeks of pregnancy allowing early screening for trisomies1,4,5 blood2,4,5
. The amount found in maternal blood increases as gestation increases1
. It comprises 3-6% of total cell free DNA in maternal . It originates from the
placenta rather than the fetus and is therefore still a screening test, not a diagnostic test, because placental mosaicism is found in about 1% of pregnancies1
needed and fetal DNA should comprise at least 4% of the total DNA in the sample1,5,6 the patient and clinician within a week4,5
(refer to table 1 for definitions). It is not a diagnostic test and gives a risk of an individual
fetus having trisomy 21. If a pregnancy has a risk higher than 1 in 150 a diagnostic test is offered. This is either an amniocentesis or chorionic villus sampling (CVS). Both of these are invasive and have a miscarriage rate of 0.5-2%. If a patient books later in pregnancy, or a nuchal thickness measurement cannot be performed, she can
undergo quadruple screening, so called because it measures four proteins in the maternal serum. These are hCG, alpha fetoprotein, unconjugated oestriol and inhibin A. This gives a detection rate of 75% with a 5% false positive rate2
.
In a multiple pregnancy, nuchal thickness can be measured for each fetus, but serum blood tests cannot be divided between the pregnancies. For monochorionic twins, a single risk is given because both twins are genetically identical. For dichorionic twins, two risks are given because the twins are likely to be genetically
-20- not meeting quality control criteria, however a repeat blood sample usually yields a result1,6 .
. There is a 1% chance of not obtaining a result due to the samples . Just as it is
harder to obtain an accurate nuchal thickness measurement with maternal obesity, this can also affect the chances of obtaining a result with ffDNA. An increase in maternal weight decreases the percentage of ffDNA in the sample making it more likely the sample will not yield a result1
Pregnancies with Down’s syndrome have higher than normal concentrations of fetal DNA from chromosome
21. A technique called massive parallel sequencing is used to increase the amount of fetal DNA available for a test and detect certain DNA sequences. There are significantly more sequences from chromosome 21 found when Down’s syndrome is present despite the fetal DNA being mixed with maternal cell free DNA1
. Shotgun
sequencing is another technique that compares the number of sequences from chromosome 21 with the number of sequences from other chromosomes and is thus able to detect trisomic pregnancies1 As discussed, placental mosaicism can still give rise to the occasional false positive result as can a
.
. In order to run the test 7-10ml of maternal venous blood is . Results are available to
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