I’d like to teach the world to sing (in perfect harmony)
– The New Seekers*
New things come along very rarely in my business. Childbirth itself defines human existence and is of course described in the most ancient of texts. The techniques we use to manage abnormal labour and birth – the ventouse, the forceps and caesarean section – have all been around for more than a century and have changed little over time. We still don’t know the exact cause of preeclampsia (high blood pressure in pregnancy) and the cure remains simply delivering the baby. Ultrasound and epidurals were discovered in the 1960s although they have improved greatly over the last decade or so. We have been sticking needles into the pregnant uterus for more than fifty years and these invasive techniques have been the mainstay of the prenatal diagnosis of fetal chromosomal abnormalities for at least as long as I have been involved in obstetrics.
Unfortunately there is a problem (as Jeremy Clarkson might say on Top Gear) with amniocentesis and chorionic villus sampling (CVS) for chromosomal abnormalities: the – admittedly very rare – risk of a miscarriage being caused by the procedure. This risk is the reason why we usually begin the prenatal testing process with a screening test that carries no risk – the Nuchal translucency (NT) test. This test was discovered in the early 1990s and is based on some very simple observations; namely that fetuses with Down syndrome – as well as those with the other common significant chromosomal abnormalities, Trisomy 18 and Trisomy 13 – have some changes that can be seen on ultrasound at around twelve weeks gestation. These changes are a thicker neck (the nuchal translucency) and an underdeveloped nose bone. When combined with some placental hormonal blood tests this ultrasound detects around 96 percent of fetuses with Down syndrome. Until recently a “high risk” NT test meant that a woman had to consider one of the invasive needle tests in order to confirm or deny whether the fetus indeed had a major chromosomal abnormality (with, of course, the attendant very small risk of a miscarriage being the result).
So we have been using the NT test along with – if necessary – the needle tests as the basis for our prenatal testing for fetal abnormalities for at least twenty years now.
…the Non Invasive Prenatal Test (NIPT) came along this year. This test is marketed by an American company as the Harmony test (hence the musical reference above*).
Now I consider myself to be a fairly smart guy and a conscientious one too. Accordingly I have read all of the scientific stuff about the NIPT and…
…I still don’t understand it!
To the best of my extremely limited understanding, it goes something like this:
- DNA is the basis of our genetic code and it is usually found in the nucleus of our cells
- Most of us have 46 chromosomes, 23 of which came from our mother and 23 from our father
- Babies with Down Syndrome have three chromosome 21s as opposed to the usual two (hence Trisomy 21)
- There are lots of other trisomies and they usually cause miscarriages. Trisomies 13 and 18 can cause the live birth of a term baby with multiple abnormalities
- It’s not fair but the “extra” chromosome that causes a Trisomy comes from the mother and the risk of a trisomy increases with the age of the mother
- (You’ll be pleased to know I’m on top of this information so far – but here comes the bit I struggle with):
- Mothers have DNA freely floating around in their blood (as do all of us, I presume)
- In addition to their own DNA freely floating around in their blood mothers also have their baby’s (or babies’ if there are twins) DNA floating around in their blood
- The source of this DNA is the placenta (remembering the placenta is the site of lots of interchange between mothers and their babies – oxygen and glucose passes to the baby while waste products pass from the baby to the mother)
- Now (and I’m really struggling here) we can now determine two things from the amounts of specific types of DNA found in the mother’s blood (sequences, if you must know):
- Whether the DNA comes from the mother or the fetus,
- Whether the baby has Down syndrome (or another of the common trisomies), and
- The gender of the baby
The NIPT has been demonstrated to be at least 99 percent accurate for the diagnosis of Down syndrome; as opposed to the 96 percent for the NT test.
I gather that the reason the NIPT is “only” 99 percent accurate for Down syndrome is because of something called placental mosaicism and rarely (you have to believe me here) the placenta can have different chromosomes to the actual baby. (This is why we would always advise a needle test to confirm the diagnosis if the NIPT indicated Down syndrome or any other significant abnormality).
The other significant advantage of the NIPT over the NT test is that the blood for the test can be taken at ten weeks gestation – the NT test is usually performed at 12 to 13 weeks (although, then again, it currently takes two weeks for the results of the NIPT to arrive – this is partly because the NIPT test is only conducted in the USA).
Oh and the NIPT will cost you around $500 and don’t expect any rebates from Medicare or your Health Fund.
OK, sounds good – so where does that leave us?
Some commentators feel the NIPT is the best thing in prenatal diagnosis since sliced bread and they are correct – up to a point.
When compared to the current NT test, the NIPT has a couple of important advantages. These are:
- It is more accurate for the diagnosis of Down Syndrome (more than 99 percent compared to 96 percent), and
- The NIPT can accurately determine the gender of the baby.
However – in my view at least – the NIPT has a couple of disadvantages when compared to the current NT test. These are:
- The NT test not only looks at Down syndrome (Trisomy 21) but Trisomy 18 and Trisomy 13 as well. At the moment the NIPT is around 98 percent accurate for Trisomy 18 but only 80 percent accurate for Trisomy 13.
- The NT – critically in my view – includes an experienced women’s health ultrasound expert scanning your baby and looking at its anatomy and checking for any associated fetal abnormalities. Most significant structural fetal abnormalities can now be detected at 12 to 13 weeks gestation on a good quality scan. Then again the ultrasound practices I work with in Sydney strongly recommend an ultrasound be performed in association with the NIPT.
- An increased nuchal translucency (i.e. a thick neck) can be associated with non – chromosomal problems including heart abnormalities and some other syndromes. This is why if a baby has a thick neck but normal chromosomes we usually organise a special scan of the baby’s heart (a fetal echocardiogram) at around 24 weeks gestation; even if all of the previous ultrasounds have been normal.
- The current NT test includes blood tests of placental hormones. One of these – the PAPP-A – also examines placental function and can help to predict some problems in late pregnancy including significant fetal growth restriction.
So – and pay attention, 007 – I DO NOT recommend replacing the NT test with the NIPT.
I consider the NIPT to be an incredibly useful addition to all the tests available but not a replacement for the NT test. Furthermore if, for any reason, the NIPT is conducted without an NT test taking place it should at least be accompanied by a careful expert ultrasound of the baby at 12 to 13 weeks gestation.
The other issue – and you don’t want to think about this too much – is say (God forbid) your NT test came back with a risk of Down Syndrome (or some other abnormality) of one in three (or one in five or one in ten – an incredibly high risk of a problem). Would you be happy to then go ahead with a test that is “only” 99 percent accurate – or would you prefer to bite the bullet and have an amnio or CVS knowing the result will be both comprehensive and accurate?
It is also worth comparing the NIPT test with the currently available invasive tests – amniocentesis and the CVS. The NIPT has the obvious advantage over the “needle” tests (amnio and CVS) that it has no risk of causing a miscarriage. On the other hand the needle tests are usually 100 percent accurate and if you undergo a needle test they can test for any and all of the genetic abnormalities of which we are currently aware (Cystic Fibrosis, haemophilia, etc.).
So far, so confusing.
OK, so what does your favourite obstetrician recommend?
I will start with what I DO NOT recommend:
I do not recommend replacing our existing tests (the NT and the needles) exclusively with the NIPT.
By the way there are women who have specific personal or family histories that necessitate specific prenatal (usually needle) tests. The NIPT – and often the NT – test is not appropriate for these women and they need to have an appropriate test for the relevant condition.
For everyone else – and having looked at some international guidelines – I suggest the following:
1. Women at higher risk of giving birth to a baby with a chromosomal abnormality:
I suggest having blood taken for the NIPT at just over ten weeks gestation and then undergoing the full NT test (including its blood tests) at twelve weeks. If the NIPT and the NT test are both normal then the chances of the baby being affected by Down syndrome are less than one in ten thousand.
Women at higher risk of giving birth to a baby with a chromosomal abnormality are those who have previously had a pregnancy affected by a chromosomal abnormality and older mothers – those older than 37 years of age.
2. Everyone else
I suggest doing what we always do. I advise undergoing the “usual” NT test and then discussing further testing once we have the NT results.
If the NT test is clearly low risk (one in 1,000 or lower) I advise no further testing until the usual fetal morphology (structural) ultrasound scan conducted at 19 weeks gestation.
If the NT test gives an extremely high risk of the baby being affected by a chromosomal abnormality (say one in 50 or higher) I recommend undergoing one of the needle tests – either a CVS or an amnio. Ultimately these tests are the most accurate we have so – notwithstanding the small degree of risk involved – they are the most accurate tests available AND we can test for abnormalities other than trisomies when they are conducted.
If the NT test gives us a result between around one in 50 and one in 1,000 (you might call this an intermediate result) I’d suggest undergoing the NIPT test before deciding upon any further action.
Now what do we do if the NIPT is abnormal?
It is important to remember the NIPT test is a screening test and not a diagnostic test. It can give what we call false positive and false negative results. If the NIPT is abnormal I recommend NOT taking any specific action immediately. My strong advice – remembering that the NIPT is “only” 99 percent accurate – is to undergo a diagnostic needle test (usually an amnio) before deciding upon any further specific action.
A couple of random points about prenatal diagnosis
- It is worth remembering that all of the tests described above are aimed at detecting whether or not your baby has a known significant chromosomal abnormality. Remember that the tests are complex, comparatively expensive, can cause significant anxiety and – if a needle is used – the risk of physical harm to a baby that could be quite normal. I suggest that if for religious or any other reasons you would not at least strongly consider specific action if your baby was proven to be abnormal that you not undergo these tests.
- Please also remember these tests mainly check for chromosomal abnormalities and as such offer no guarantee your baby is normal. The 19 week scan checks for fetal structural abnormalities that can occur even if the baby has normal chromosomes. In addition we have no prenatal tests for conditions such as cerebral palsy, autism or wanting to go to Law School.
- As I have said a couple of times these tests cost a fair amount of money. Some couples are tempted to have their prenatal testing done at the less expensive general radiology clinics in town. I feel this is a false economy. The specialised Women’s Health Ultrasound centres in Sydney are – in my view – better at detecting subtle problems on ultrasound than other places and they are also very good in the manner in which they communicate their findings with both you the customer and me the referring obstetrician. This is because the sonographers and doctors in such specialised practices do women and babies all week long. They are not doing ultrasounds of male abdomens or chest X-rays and the like. Accordingly their expertise, equipment and experience are focussed on women and their unborn babies. This expertise is also the reason why the risk of a miscarriage following a needle test is much lower than it used to be when general radiologists and obstetricians performed amniocenteses.
Watch this space!
The field of non-invasive prenatal testing is moving forward at a very rapid rate. I’m sure new tests will become available soon.
Dr Fergus Scott is a women’s health ultrasound expert at Sydney Ultrasound for Women. He has lots and lots of letters after his name. Fergus has kindly peer reviewed this information sheet and I have incorporated all of his suggested changes. However the opinions expressed in this sheet are mine and I am solely responsible for any errors.
* The song “I’d like to teach the world to sing (in perfect harmony)” is interesting (according to Wikipedia). Most advertising jingles or songs are popular songs that are successful songs which are then adapted to an ad. In this case the reverse occurred. A couple of canny ad execs wrote the “song” “I’d like to buy the world a Coke” and turned it into a MASSIVE Coke ad. (You’re all too young to remember but at the time it was the most expensive TV ad made until that time). Anyway – and unusually – The New Seekers (again, you’re too young) turned the ad into the popular “I’d like to teach the world to sing, sing in perfect harmony – grow apple trees and honey bees and snow white turtle doves…”