Screening

Screening for Chromosomal Abnormalities in Pregnancy

In early pregnancy you will be offered screening for the common chromosomal abnormalities such as Trisomy 21 (Down syndrome), Trisomy 18 (Edwards syndrome) and Trisomy 13 (Patau syndrome). These abnormalities usually occur due to abnormal cell division of the fertilised egg at the time of conception, and are more common as the woman ages.

The risk for giving birth to a baby with Trisomy 21 is about 1:1500 when a woman is 20 years old, and this risk increases to 1:100 by the age of 40. Down syndrome is associated with intellectual and some physical disabilities.  Babies with Trisomy 13 and 18 are associated with more severe intellectual and physical disabilities and are more likely to die during or after pregnancy.

Non Invasive Prenatal Testing (NIPT)

Non Invasive Prenatal Testing (NIPT) is a high level screening test for identifying pregnancies with increased chance of chromosomal abnormalities.

NIPT has revolutionised the way we screen for Down syndrome (Trisomy 21) and it is the most accurate screening test available.

NIPT can identify more than 99% of pregnancies where the fetus has Down syndrome.

NIPT can also identify pregnancies at an increased risk of Edward syndrome (Trisomy 18), Patau syndrome (Trisomy 13) and sex chromosome conditions such as Turner syndrome (Monosomy X) and Klinefelter syndrome (XXY).

You can also find out the fetal gender, with 99% accuracy, if you wish to know.

NIPT can be performed on single and twin pregnancies and those arising from IVF treatment or egg donation.

How is NIPT performed?

A blood sample is taken from the pregnant woman after 9-10 weeks of pregnancy.

In pregnancy, the mothers blood contains small amounts of fetal DNA.  This is produced and released by the placenta.  The amount increases as the pregnancy progresses.  This is called cell-free DNA.

 

The sample is analysed for an increasing number of genetic conditions.

Which NIPT is performed at WUMe?

There are several trade names for NIPT and it can be confusing which test to have.

All NIPT brands screens for the major chromosome abnormalities involving chromosomes 21, 18, 13, X and Y.

At WUMe, we offer two brands of NIPT:

1. The Harmony Prenatal Test

The Harmony Prenatal Test has been performed in close to 1 million pregnancies in the USA and has the most publications to support its performance.

Harmony can detect:

  • >99% of fetuses affected with Trisomy 21 (Down syndrome), with a false positive rate of <0.1%
  • 97.4% of fetuses affected with Trisomy 18 (Edwards syndrome), with a false positive rate of <0.1%
  • 92.8% of fetuses affected with Trisomy 13 (Patau syndrome), with a false positive rate of <0.1%

The combined false positive rate for this standard panel group (Trisomy 21, 18, 13) is less than 0.3%.

Fetal Sex can also be reported on, should you wish to know.

The cost of the Harmony Prenatal Test is $430    (additional $20 collection fee applies at FPH)

This includes:
Standard panel screening:
Trisomy 21 (Down syndrome, T21)
Trisomy 18 (Edwards syndrome, T18)
Trisomy 13 (Patau syndrome, T13)

Optional additions at no extra cost:
Add fetal sex only
Add Monosomy X
Add Sex Chromosome Aneuploidy (SCA) panel

This test is performed in Australia and results are available within 5 to 8 working days.

2.Panorama Prenatal Test

Panorama Prenatal Test is also available at WUMe.

Panorama also screens for chromosome abnormalities involving chromosomes 21, 18, 13, X and Y- the same standard panel as Harmony.

In addition to standard panel screening, Panorama can screen for microdeletions.  Microdeletions are caused when a chromosome is missing a small piece. The severity of problems caused by a microdeletion is determined primarily by the size and location of the deletion.  Developmental delay issues and structural anomalies are also common with these disorders.

Panorama screening options are:

  • Standard panel  screening + 22q

22q syndrome, known as Di George or Velocardiofacial syndrome, which affects 1 in every 2000 newborns, in combination with standard panel screening (Trisomies 21, 18, 13, X and Y)

or

  • Standard panel screening as part of the Five Microdeletion Panel

(22q syndrome, 1p36 syndrome, Cri du Chat syndrome, Angelman syndrome and Prader-Willi syndrome.

The cost of Panorama standard panel screening plus 22q is $510     (additional $20 collection fee applies at FPH)
This includes:
Standard screening panel:
Trisomy 21 (Down syndrome, T21)
Trisomy 18 (Edwards syndrome, T18)
Trisomy 13 (Patau syndrome, T13)
Monosomy X
Triploidy
22q (Di George/Velocardiofacial syndrome)

The cost of Panorama standard panel screening plus 5 microdeletion panel is $630    (additional $20 collection fee applies at FPH)

This includes:
Standard screening panel:
Trisomy 21 (Down syndrome, T21)
Trisomy 18 (Edwards syndrome, T18)
Trisomy 13 (Patau syndrome, T13)
Monosomy X
Triploidy
22q (Di George/Velocardiofacial syndrome)
1p36 syndrome
Cri du Chat syndrome
Angelman syndrome
Prader-Willi syndrome

Some women may choose to have the more extensive screening panel as they become aware of the greater options available.  It is advisable that if you wish to have screening for 22q as part of the standard panel or as one of the Five Microdeletion Panel, your doctor should specify this on your referral.

Panorama samples will be sent to the USA for analysis and the results will take a few days longer than the Harmony Prenatal Test.

When do I have NIPT?

NIPT is part of the assessment for fetal abnormality in the first trimester of pregnancy. All women are offered screening for fetal abnormality between 9 and 14 weeks of pregnancy.

WUMe recommends a combination of NIPT from 9-10 weeks onwards and an early fetal anatomy ultrasound performed at 12-13 weeks of pregnancy. The combination of NIPT and a 12-13 week ultrasound maximises the detection of fetal abnormality at this early gestation.

There is an overlap between NIPT and the ultrasound. Most fetuses with Down syndrome will be detected by both tests. However, each test detects some abnormalities that may be missed by the other, and so it is optimal to have both.

Can I find out the fetal sex?

You can choose to screen for fetal sex.  You may choose whether this information is disclosed to you or not.
If you wish to know the fetal sex, NIPT will look for Y (male) chromosome. If it is present the sex will be reported as a male and if it is not present the sex will be reported as a female.

You will also be asked if you want to test for sex chromosome abnormalities such as Monosomy X (Turner syndrome) or Kleinefelter syndrome. Both these conditions have infertility and other health issues.

What do the results mean?

Both the Harmony and Panorama tests report either a high or low risk.

A “Low Risk” result indicates a significantly reduced chance that your fetus has the chromosome abnormalities which have been tested for. It does not mean that the chromosomes will definitely be normal or that the baby is guaranteed to be healthy. For example, a low-risk result for Trisomy 21 is reported as having a less than 1 in 10,000 chance of having a baby with Down syndrome.

A “High Risk” result indicates that there is a significantly increased likelihood that your fetus has one of the chromosomal abnormalities tested for, but it does not confirm that the fetus has that chromosomal abnormality. For example, a high risk result for Trisomy 21 is reported as having a 99 out of 100 chance of having a baby with Down syndrome.

Confirmation of a high risk result will be invasive prenatal diagnostic testing or by testing the baby after delivery if this is your choice.

What if NIPT fails to give a result?

There is a chance that samples sent for NIPT will not return a result.

In 2-3% of samples, the laboratory is unable to give you a result from the first blood collection. If this happens, you will be asked to provide another blood sample for analysis. A result is successful in 2 out of 3 cases where a second sample is collected.

Usually, a sample does not yield a result due to a low fetal fraction. Fetal fraction is the proportion of cell-free DNA in the pregnant woman’s blood. Cell free DNA is of fetal (placental) origin. Test accuracy and reliability is reduced at low fetal fractions. For this reason results are not issued using Harmony with a fetal fraction of under 4%.

Fetal fraction will be lower when the pregnancy is less advanced than expected by dates, when the pregnancy has failed to grow, in women who have a high Body Mass Index (BMI) or due to other maternal factors.

It is important to understand that if NIPT is unable to give a result from your first sample, “back up” screening will be arranged by WUMe. A second blood sample will be taken for NIPT, as well as for MSS (Maternal Serum Screen). The MSS must be taken before 13 weeks and 6 days of pregnancy.

If the second NIPT sample fails to provide a result, CFTS (MSS combined with the 12–13 week ultrasound), will then provide the most accurate screening available.

Combined First Trimester Screening (CFTS)

An alternative screening test for Down syndrome is the Maternal Serum Screen (MSS) combined with a 12-13 week ultrasound.  The ultrasound uses measurement of Nuchal Translucency (NT), a developmental layer of fluid behind the fetal neck which is present from 11 to 14 weeks, together with other ultrasound markers for chromosomal abnormalities.  This is analysed statistically against pregnancy proteins in the pregnant woman’s blood using the Fetal Medicine Foundation algorithm (www.fetalmedicine.com).

This test has a ~90% detection rate for Down syndrome, and has been widely used for many years. It provides an individualised risk for each fetus in multiple pregnancy and also provides a risk for Trisomy 18 and 13. This test is gradually being superseded by the Non Invasive Prenatal Test (NIPT) and ultrasound.

The major advantage of CFTS is that the cost is less than the NIPT test and attracts a Medicare rebate for both the ultrasound and MSS.

A high risk result occurs in approximately 4% of all women screened and if this occurs you will receive counselling about the result and about diagnostic testing (Chorionic Villous Sampling (CVS) or Amniocentesis).  With some results, NIPT may be a suitable next step following a high risk CFTS.

 

Ultrasound Alone

Ultrasound uses measurement of NT between 12-14 weeks of pregnancy, together with other ultrasound markers for chromosomal abnormalities, to calculate a statistical risk for Down syndrome.  This is based on extensive research by the Fetal Medicine Foundation (www.fetalmedicine.com).

All WUMe doctors are accredited by the Fetal Medicine Foundation which requires regular individual audit.

The detection rate for Down syndrome using ultrasound alone is approximately 70%.  Addition of MSS increases the detection rate of Down syndrome to ~90%.

NIPT detection rate for Down syndrome is >99%.

 

Which test for Down syndrome should I have?

There are 3 test available for Down syndrome:

  1. CVS and Amniocentesis-These tests are considered diagnostic. Invasive, or needle testing, remains the gold standard for Down syndrome and all other chromosomal abnormalities.
  2. NIPT a screening blood test that will detect >99% of Down syndrome
  3. CFTS involves taking a blood test called the Maternal Serum Screen (MSS) and combining it with the 12-13 week ultrasound and Nuchal Translucency Measurement to create a risk for Down syndrome. This test will detect ~90% of Down Syndrome.
Deciding whether or not to have NIPT and when

NIPT is a limited screening test, it is not diagnostic.

NIPT is not able to provide a definite result for Down syndrome. It does not assess all the chromosomes as is done with CVS or Amniocentesis.

It is important to remember that even with a low risk result from NIPT, a 12 – 13 week ultrasound is highly recommended, as structural abnormalities and/or increased Nuchal Translucency may be detected which would lead to consideration of further testing.

NIPT is more costly than the older CFTS but does offer a higher detection rate for Down syndrome of >99% versus 90%.

Some women choose to have the combined 12-13 week ultrasound and MSS first and then make a decision about having NIPT. This is called contingency screening and may be a more cost-effective approach for younger mothers.

For women with a high risk CFTS where the Nuchal Translucency and fetal anatomy are normal on ultrasound, NIPT can offer increased screening accuracy and provide the option of avoiding invasive testing with a higher level of reassurance.

For those women who seek definitive diagnosis – invasive testing is the answer.

What are the limitations of NIPT?

Low risk result on NIPT but ultrasound shows a structural abnormality-
If the ultrasound shows a structural (physically visible) abnormality at any stage during the pregnancy, you will likely be offered an invasive test despite having had NIPT. This is because NIPT is for a very limited range of chromosome problems. If the Nuchal Translucency is increased at the 12-13 week ultrasound, you will also likely be offered an invasive test.

NIPT is a screening test –
It is not a diagnostic test. This means that it is possible for a fetus to have Down syndrome even if the NIPT result is low risk (false-negative). It is also possible for a fetus NOT to have the condition if labelled high risk (false-positive), therefore a diagnostic test (CVS or amniocentesis) is required to confirm the diagnosis

No NIPT result –
In 1-4% of cases, the laboratory is unable to give you a result from the first blood collection. If this happens, a repeat blood sampling is successful in 2 out of 3 cases.

Accuracy of Fetal Sex and Sex Chromosome Abnormalities –
Correct assessment of the fetal sex (female or male) is less accurate than Down syndrome screening with NIPT. This is because there are more variations in human sex chromosomes than other chromosomes.

NIPT is also less accurate for Sex Chromosome Abnormalities (SCA) as it is harder to assess the amount of X chromosome against the background of the pregnant woman who has 2 X chromosomes of her own. The SCA include Turner syndrome (Monosomy X) and Klinefelter syndrome (XXY). The detection rate for SCAs is lower than for Trisomy 21, Trisomy 18 or Trisomy 13, however, the exact figure is not known as this would require all newborn babies to be tested.

Additionally NIPT gives a high risk result in some cases where there is no SCA present in the fetus, and this happens more often than it does for Trisomy 21, 18, 13. To clarify this before birth an amniocentesis or CVS would need to be performed. This is why SCA screening is an optional part of NIPT.