Non-invasive prenatal testing (NIPS) has emerged as a high-accuracy screening test for chromosomal abnormalities in pregnancy. NIPS can be ordered as early as 10 weeks in the pregnancy and offers a higher sensitivity and a lower false positive rate than the traditional combined first trimester screening test.
Approximately one in 150 live births are affected
by a chromosomal abnormality. Although it is well
understood that the risks of chromosome problems
in pregnancy increase with maternal age, all
pregnancies, regardless of maternal age, could be
affected.1 Hence, screening or diagnostic testing for chromosomal abnormalities should be discussed and
offered to all pregnant women.
The most common chromosomal abnormality is
Down syndrome, which occurs at a prevalence of
approximately one in 800 live births.1 In the last few decades, clinicians in Singapore have seen prenatal
screening for Down syndrome transition from being
part of the second trimester triple test to the combined
first trimester screening test.
The combined first trimester screening test has been
routinely offered to patients at KK Women’s and
Children’s Hospital (KKH) for the past 15 years. It takes
into account maternal age, maternal serum markers
(free β-hCG and PAPP-A) and ultrasound markers of the fetal nuchal translucency measurement and
assessment of the fetal nasal bone, to reach a 90%
detection rate for Down syndrome at a false positive
rate of 5%.
More recently in 2011, Down syndrome screening
experienced a paradigm shift through the introduction
of the analysis of cell-free DNA (cfDNA), which is
derived from the placenta that circulates in the
This method of testing is also known as non-invasive
prenatal screening (NIPS) and is often referred to by
the general public by the various test names of different
commercial companies (e.g., Harmony, Panorama).
Compared to the combined first trimester screening
test, NIPS has a higher accuracy and is able to
achieve an over 99% detection rate for Down
syndrome at a 0.04% false positive rate.
NIPS is an optional blood test that can be performed
during pregnancy. Conditions primarily tested for
through NIPS include Down syndrome, trisomy 18,
trisomy 13 and chromosomes X and Y. Expanded
screening for other chromosome defects may also
NIPS involves the assessment of cfDNA that is
derived from the placenta that circulates in the
maternal blood. The cfDNA is quantified through
whole genome sequencing, targeted sequencing or
targeted microarray. The sample is then identified as
“high risk” or “screen positive” if the proportion of DNA
sequences from a particular chromosome is found to
The amount of cfDNA in the peripheral blood of a
pregnant woman is usually sufficient for analysis from
as early as 10 weeks of gestation until term. This
cfDNA accumulates with gestation and is cleared from
the maternal circulation within hours after childbirth.
Hence, the result of NIPS for the current pregnancy
would not be affected by cfDNA from any previous
NIPS provides a very accurate assessment of the
risks of Down syndrome, trisomy 18 and trisomy 13 in
the pregnancy through the analysis of the blood of a
pregnant woman, drawn via venepuncture.
Based on a recent meta-analysis of 35 relevant studies,
the weighted pooled sensitivities of NIPS were 99.7%
for Down syndrome, 97.9% for trisomy 18 and 99.0% for
trisomy 13. The pooled false positive rate was 0.04%.2
NIPS is clearly a more accurate test with a higher
sensitivity and a lower false positive rate compared
to traditional methods of screening such as the combined first trimester screening test.
Despite its high accuracy for Down syndrome,
trisomy 18 and trisomy 13, NIPS is still considered
a screening test and false positive and negative results can still occur. There could be several
reasons for false positive and false negative
results including discordance between placental
and fetal chromosomes, fetal mosaicism, maternal
chromosomal abnormality or variation, low fetal
fraction and a vanishing twin.A “low risk” or “screen negative” result through
NIPS indicates a decreased risk for the condition
but does not rule out the possibility of the condition
in the pregnancy, while a “high risk” or “screen
positive” result indicates an increased risk for the
condition but is not confirmatory either. Hence,
follow-up diagnostic testing through invasive
testing (chorionic villus sampling or amniocentesis)
may be subsequently offered for confirmatory
Although NIPS tests for the common chromosomal
aneuploidies, the list of chromosome problems is
not exhaustive and varies between commercial
companies. Furthermore, the accuracy of the
conditions screened for through NIPS depends on
the condition that is assessed and the platform
that is used.
Since NIPS is a blood test, it does not involve an
ultrasound of the pregnancy and is thus unable to
screen for structural defects or markers that may or may not be related to chromosome defects in
the fetus. Hence, it is still important to offer prenatal
ultrasound scans to all pregnant women to help
screen for structural defects or markers, which may suggest testing beyond the few conditions that are
covered through NIPS.
Furthermore, testing of some samples through
NIPS may not produce any results and be
marked as “inconclusive”. This occurs in 0.03–
11% of samples2 and may be due to technical or
biological reasons. A subsequent redraw of the
pregnant woman’s blood, in hopes of producing a
result, may or may not be possible.
Testing through NIPS has also been extended
to twin pregnancies, but its performance is
less extensively validated compared to that of
singleton pregnancies. NIPS is also not suitable
for pregnancies with a co-twin demise, a vanishing twin or an empty second sac.
If a patient expresses interest in NIPS, she may be referred to KKH for an appointment with an obstetrician. This will involve:
Besides taking a detailed pregnancy history, the obstetrician will also arrange for an ultrasound scan to be done to determine important details of the pregnancy before NIPS is performed. NIPS is performed in-house at KKH, using the Harmony prenatal test. By being run locally, Harmony allows more efficient reporting of results and better communication between the laboratory and the ordering physician.
Prenatal genetic counsellingBesides laboratory services, KKH also provides patients with prenatal genetic counselling services to help them better understand the details of NIPS as well as other test options that may be available. Prenatal genetic counselling is an integral part of obstetric care.
Although NIPS is a highly accurate test for the common chromosomal aneuploidies, it must be offered and considered carefully in order for pregnant women to exercise their reproductive autonomy and make informed decisions about their pregnancies.
The feasibility of extending NIPS beyond the common aneuploidies has been demonstrated. The use of NIPS for monogenic disorders such as thalassemia is widely anticipated, especially by patients with family histories of certain monogenic disorders and who are reluctant to pursue invasive diagnostic testing. The many technical and analytical challenges associated with NIPS for monogenic disorders are currently being worked out, and hopefully with thorough validation and cautious implementation, NIPS for monogenic disorders will be an option that is clinically available to pregnant women in the future.
Christina Choi, MS, CGC is the Senior Principal Genetic Counsellor at the Antenatal Diagnostic
Centre at KK Women’s and Children’s Hospital (KKH). She joined KKH in 2012, and as a prenatal
genetic counsellor with the Fetal Medicine team, uses her knowledge in medical genetics and
understanding of the psychosocial impact of communication to provide genetic counselling to
high-risk pregnancies. She also leads a team of nurse counsellors and oversees the execution
of prenatal chromosomal/genetic testing at the Antenatal Diagnostic Centre at KKH.
Ms Choi received her B.A. in Biology and M.S. in Biotechnology from Johns Hopkins University
and went on to obtain her M.S. in Genetic Counselling from Boston University School
of Medicine. She continued to work in the San Francisco Bay Area as a prenatal genetic
counsellor at a private obstetrics practice and was also involved in early startup days of
technology company Counsyl Inc. She is board certified with the American Board of Genetic
GPs can call the SingHealth Duke-NUS Genomic Medicine Centre for appointments at the following hotlines:KK Women's and Children's Hospital: 6692 2984National Cancer Centre Singapore: 6436 8288
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