Ethical considerations when offering noninvasive prenatal testing

Technology in the prenatal setting is advancing at an exceptional rate, and these advancements will likely result in major changes to current pregnancy screening and testing paradigms. In Australia, prenatal testing is increasingly becoming a routine part of antenatal care and pregnant women are offered an assortment of screening and diagnostic tests, which give them information about their fetus, and can identify potential anomalies before it is born. In Victoria (Australia), each year approximately 4% of babies will be born with a birth defect or fetal abnormality many of which are diagnosed in uterus. Greater than 97% of women in Victoria have at least one or more ultrasounds during pregnancy and greater than 80% of pregnant women take up screening for Down syndrome, with the majority having First Trimester Combined Screening (FTCS). FTCS combines maternal serum analytes — pregnancy associated plasma protein-A (PAAP-A) and beta human chorionic gonadotrophin (free β-hCG) — with results from the nuchal translucency ultrasound to give a risk figure for Down syndrome and Trisomy 18. Approximately 5% of women will receive a false positive result from FTCS, meaning they screen positive for Down syndrome or Trisomy 18 and do not have an affected pregnancy. Women who are considered to be “increased risk” either because of a screening result or ultrasound finding are offered invasive diagnostic testing whereby a fetal sample is obtained via chorionic villus sampling (CVS) or amniocentesis and sent for conventional or molecular karyotyping (microarray). These tests carry a miscarriage risk of up to 1% above the background rate of miscarriage. There has been increasing demand for a safe and reliable alternative to invasive diagnostic testing and very recently, noninvasive prenatal testing (NIPT) has become commercially available to women in America (2012), Australia and many other countries, including Brazil (2013). NIPT is an advanced screening test, which relies on the fact that small fragments of cell-free fetal DNA and RNA circulate in maternal serum. In the first and second trimesters of pregnancy, approximately 6–10% of total cell free DNA (cfDNA) circulating in maternal serum is thought to be fetal in origin; this fetal fraction rises to 10–20% in the third trimester. Using massively parallel sequencing technology, scientists can sequence cfDNA fragments in maternal plasma and detect specific chromosome aneuploidies such as trisomies 21, 13 and 18, much earlier in pregnancy than has previously been possible,

Technology in the prenatal setting is advancing at an exceptional rate, and these advancements will likely result in major changes to current pregnancy screening and testing paradigms.In Australia, prenatal testing is increasingly becoming a routine part of antenatal care and pregnant women are offered an assortment of screening and diagnostic tests, which give them information about their fetus, and can identify potential anomalies before it is born.In Victoria (Australia), each year approximately 4% of babies will be born with a birth defect or fetal abnormality 1 many of which are diagnosed in uterus.
Greater than 97% of women in Victoria have at least one or more ultrasounds during pregnancy 2 and greater than 80% of pregnant women take up screening for Down syndrome, with the majority having First Trimester Combined Screening (FTCS).FTCS combines maternal serum analytes -pregnancy associated plasma protein-A (PAAP-A) and beta human chorionic gonadotrophin (free β-hCG) -with results from the nuchal translucency ultrasound to give a risk figure for Down syndrome and Trisomy 18.Approximately 5% of women will receive a false positive result from FTCS 3 , meaning they screen positive for Down syndrome or Trisomy 18 and do not have an affected pregnancy.
Women who are considered to be "increased risk" either because of a screening result or ultrasound finding are offered invasive diagnostic testing whereby a fetal sample is obtained via chorionic villus sampling (CVS) or amniocentesis and sent for conventional or molecular karyotyping (microarray).These tests carry a miscarriage risk of up to 1% above the background rate of miscarriage 4 .
There has been increasing demand for a safe and reliable alternative to invasive diagnostic testing and very recently, noninvasive prenatal testing (NIPT) has become commercially available to women in America (2012), Australia and many other countries, including Brazil (2013).NIPT is an advanced screening test, which relies on the fact that small fragments of cell-free fetal DNA and RNA circulate in maternal serum 5 .In the first and second trimesters of pregnancy, approximately 6-10% of total cell free DNA (cfDNA) circulating in maternal serum is thought to be fetal in origin; this fetal fraction rises to 10-20% in the third trimester 6,7 .Using massively parallel sequencing technology, scientists can sequence cfDNA fragments in maternal plasma and detect specific chromosome aneuploidies such as trisomies 21, 13 and 18 [8][9][10][11][12][13][14][15][16][17] , much earlier in pregnancy than has previously been possible, and without having to perform an "invasive" procedure.There are currently five different companies marketing NIPT to obstetricians and pregnant women in Victoria.A summary of the key features of each test can be found in Table 1.
There are many advantages to NIPT, the most significant of which, is that it provides highly accurate information about Down syndrome without a miscarriage risk.Thus it is likely to reduce the number of invasive tests being performed.However, there are also a number of ethical considerations, which need to be taken into account when implementing NIPT in clinical practice.

Is the Noninvasive Prenatal Testing affordable?
The cost of noninvasive testing is currently prohibitive for many Australians.The most economical test retails at $850 AUD (~ $890 USD) with the other four tests retailing from $1,250-1,450 AUD ($1,300 to $1,500 USD).Currently there are no subsidies provided by Australia's government funded universal healthcare system (Medicare) or by any of the private health insurance providers so these costs are wholly paid by the patient.While it is likely NIPT will become more cost effective in the future, the current pricing raises equity concerns as women who cannot afford the test are at a disadvantage.

It is important that women and their referring doctors understand the limitations of the Noninvasive Prenatal Testing
NIPT is an advanced screening test and while the sensitivity is high (i.e.>99% for Down syndrome), it does not provide a definitive result.The false positive rate is approximately 1% and thus, patients who received a positive result for aneuploidy are advised to have prenatal diagnosis to confirm this result.The origin of the cell free fragments of fetal DNA is thought to be from placental trophoblast cells 5,18 , therefore there is a risk of confined placental mosaicism 18 .Equally, where no aneuploidy is detected, there is a residual risk that the pregnancy may be affected.
The resolution of NIPT is not as high as current diagnostic testing however, this will likely improve in the future.Current NIPT providers are offering detection of Trisomy 21, 18, 13 and in some cases sex chromosome aneuploidy.In contrast, conventional karyotyping provides structural and numerical information on all 23 pairs of chromosomes, which means many abnormalities currently detected by karyotyping will not (at present) be detected with NIPT.Furthermore, molecular karyotyping (microarray) has become the first tier test in Victoria for prenatal patients with abnormal ultrasound findings 19 .Array based technology provides a significantly higher resolution (100 fold increase) when compared with conventional karyotyping 20,21 .It is able to detect copy number variants (gains or losses in DNA) across the genome and provides increased detection of "pathogenic" and "likely pathogenic" abnormalities 19 .There has been suggestion that array based technology should be the first tier test for all patients having prenatal diagnostic testing 22 .It can provide useful clinical information, which will not be detected with current NIPT technology.Thus, it is important patients are making informed decisions about NIPT and about the detail of information they want to receive about their pregnancy, balanced with the miscarriage risks of invasive diagnostic testing.Where ultrasound examination has identified structural abnormalities or multiple soft markers, array-based technology should be recommended in preference to NIPT as it will provide the most comprehensive clinical information.

Table 1 .
Summary of noninvasive prenatal tests available in Melbourne(April, 2013)