cfDNA, ala NIPT

Oh no another acronym change!

Technically non-invasive prenatal testing aka NIPT was always a misnomer as a needle into your arm is still invasive. Now it seems we need to get used to cell free DNA testing or cfDNA. Again  technically the test is done on circulating cell-free fetal DNA which is really ccffDNA, but lets keep it shorter. An important consideration is most of the DNA comes from dead placental cells which means a discordant NIPT  oops cfDNA, may arise with mosaicism.

For a great update on what this tests and what it does have a look at this ANZJOG paper published this month.

Some highlights for cfDNA:

  • screening is suitable as a primary screening test for all women – if they can afford it (see below)
  • screening has a sensitivity of ~99% and specificity of >99% for trisomy 21 ie.,  very high detection rate and very low false positive rate (0.1%). It is only marginally less sensitivity for trisomy 18 and 13
  • sensitivity and specificity are less precise for twin pregnancies
  • does not correct guarantee correct gender and may not be as useful for sex chromosome aneuploidy
  • less sensitive for microdeletions and trisomies
  • is a screening test, it is not diagnostic. Victorian women with a high probability cfDNA result, fetal aneuploidy was confirmed by invasive fetal testing in 64%, with 36% of results being false positives
  • is useful as follow‐up screening following non-reassuring combined first trimester screen (CFTS) prior to an invasive diagnostic testing, ie. amniocentesis
  • first trimester ultrasound has benefits in addition to aneuploidy detection, including confirmation of dates, viability, number of fetuses and detection of structural anomalies. Although many women will have an ultrasound prior to paying for the cfDNA test to ensure accurate dates.
  • the required fetal fraction threshold for cfDNA ranges from 2–4%. The higher the fetal fraction the more accurate the test, hence the test is recommended after 10 weeks. Maternal weight may reduce the fetal fraction (7% in women over 100 kg and 50% over 160 kg)
  • delaying cfDNA until 12 weeks will reduce the costs of screening aneuploid pregnancies that are destined to miscarry eg., 6% of trisomy 21 pregnancies
  • cfDNA screening performs better than CFTS for aneuploidy detection thus CFTS is not recommended as this increases the false positive rate but not the detection rate
  • ultrasound ‘soft markers’ of aneuploidy need no longer be considered indications for invasive testing if the woman has had a low probability cfDNA result
  • meta‐analysis has shown procedure‐related miscarriage risks following invasive as 0.11% (one in 909) for amniocentesis and 0.22% (one in 454) for chorionic villus sampling. If doing an invasive test, I would always ask the doctor doing it what their own rates are.

Cost for the basic NIPT/cfDNA test do vary a little but have become a lot less expensive since they were introduced into Australia.

Percept from Victorian Clinical Genetic Service $449 (but needs to be done as a specific collection centre, so travelling to the collection centre needs to be factored in)

Harmony from Sonic Genetics (and 12 affiliated pathology labs) $425

Generation from Dorovitch/Laverty/QML/Western Pathology $395

Panorama from IVF Australia and (affiliated IVF services in NSW, Qld and Victoria) $450

The expanded tests for each of these assessing gender and microdeletion etc, obviously cost more. None offer a money back guarantee for errors in gender assessment! Some offer a free retest if fetal fraction is too low and no result can be give.

The cost of a cfDNA is however a considerable expense for many patient. For example, Lisa Hui has has shown that over 90% of referrals for an NIPT in 2013 were from private practice. Susan Maxwell in an editorial in the ANZJOG has called for consideration of public funding for NIP/cfDNA testing.  MBS provides a subsidy for maternal serum screening and combined first trimester screening as well as invasive prenatal diagnostic procedures and karyotyping. Although, as many families may discover there may be a considerable gap to these tests too.

I do wonder given there are 300,000 successful pregnancies in Australia each year, what cost the various pathology labs would charge if there was public funding available. Economy of scales that work for pizza should provide a more equitable solution to providing a better quality test to Australian families.