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MEDICAL POLICY 4.01.21
Noninvasive Prenatal Screening for Fetal Aneuploidies and
Microdeletions Using Cell-Free Fetal DNA
BCBSA Ref. Policy: 4.01.21
Effective Date: Oct. 1, 2017
Last Revised: March 9, 2018
Replaces: N/A
RELATED MEDICAL POLICIES:
12.04.116 Invasive Prenatal (Fetal) Diagnostic Testing
Select a hyperlink below to be directed to that section.
POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING
RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | APPENDIX |
HISTORY
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Introduction
Chromosomes are found in each cell and hold all of the genetic
material the DNA of each
person. Each cell usually contains 23 pairs of chromosomes,
including the pair that determines
the persons sex. Having more or fewer chromosomes known as
aneuploidy results in birth
defects. Screening for aneuploidies is recommended during
pregnancy. In the past, this
screening was typically done by examining cells from the fetus.
The cells were obtained either by
taking a sample of the placenta or the amniotic fluid
surrounding the baby. Newer tests that
require only a blood sample from the mother can be used to
screen for aneuploidies. This test
looks at pieces of the fetuss DNA thats naturally circulating in
the mothers blood. This policy
describes when this type of blood test may be medically
necessary. This blood test is
investigational unproven when its used to look for missing
pieces of chromosomes that
are too small to be seen without a microscope. Its also
investigational when its used early in the
pregnancy to look at the sex chromosomes.
Note: The Introduction section is for your general knowledge and
is not to be taken as policy coverage criteria. The
rest of the policy uses specific words and concepts familiar to
medical professionals. It is intended for
providers. A provider can be a person, such as a doctor, nurse,
psychologist, or dentist. A provider also can
be a place where medical care is given, like a hospital, clinic,
or lab. This policy informs them about when a
service may be covered.
https://www.premera.com/medicalpolicies/12.04.116.pdf
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Policy Coverage Criteria
Testing Medical Necessity Trisomy 21 Nucleic acid
sequencingbased testing of maternal plasma
(MaterniT21, verifi, Harmony, Panorama) for trisomy 21
may be considered medically necessary in women with
singleton pregnancies undergoing screening for trisomy 21.
Trisomy 13 and/or 18 Concurrent nucleic acid sequencingbased
testing of maternal
plasma for trisomy 13 and/or 18 may be considered medically
necessary in women who are eligible for and are undergoing
nucleic acid sequencingbased testing of maternal plasma for
trisomy 21.
Testing Investigational Trisomy 21 Nucleic acid sequencingbased
testing of maternal plasma for
trisomy 21 is considered investigational in women with twin
or
multiple pregnancies.
Trisomy 13 and/or 18 Nucleic acid sequencingbased testing of
maternal plasma for
trisomy 13 and/or 18, other than in the situations specified
above, is considered investigational.
Fetal sex chromosome
aneuploidies
Nucleic acid sequencingbased testing of maternal plasma for
fetal sex chromosome aneuploidies is considered
investigational.
Microdeletions Nucleic acid sequencing-based testing of maternal
plasma for
microdeletions is considered investigational.
Documentation Requirements The patients medical records
submitted for review for all conditions should document that
medical necessity criteria are met. The record should include
the following:
Documentation of singleton pregnancy
Coding
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Code Description
CPT 0009M Fetal aneuploidy (trisomy 21 and 18) DNA sequence
analysis of selected regions using
maternal plasma, algorithm reported as a risk score for each
trisomy
81420 Fetal chromosomal aneuploidy (eg, trisomy 21, monosomy X)
genomic sequence
analysis panel, circulating cell-free fetal DNA in maternal
blood, must include analysis
of chromosomes 13, 18 and 21
81422 Fetal chromosomal microdeletion(s) genomic sequence
analysis (eg, DiGeorge
syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA
in maternal blood
81479 Unlisted molecular pathology procedure
81507 Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence
analysis of selected regions
using maternal plasma, algorithm reported as a risk score for
each trisomy
81599 Unlisted chemistry procedure
84999 Unlisted chemistry procedure
Note: CPT codes, descriptions and materials are copyrighted by
the American Medical Association (AMA). HCPCS
codes, descriptions and materials are copyrighted by Centers for
Medicare Services (CMS).
Related Information
This policy refers to non-invasive testing and does not apply to
pregnancies with a high clinical
suspicion of fetal microdeletions for which invasive
confirmatory testing is indicated (see
Related Policies).
In a 2015 committee opinion, the American College of
Obstetricians and Gynecologists (ACOG)
recommends that all patients receive information on the risks
and benefits of various methods
of prenatal screening and diagnostic testing for fetal
aneuploidies, including the option of no
testing.
Studies published to date on non-invasive prenatal screening for
fetal aneuploidies report rare
but occasional false positives. In these studies, the actual
false-positive test results were not
always borderline; some were clearly above the assay cutoff
value, and no processing or
biological explanations for the false-positive results were
reported. False-positive findings have
been found to be associated with factors including placental
mosaicism, vanishing twins, and
maternal malignancies. In its 2015 committee opinion, ACOG
recommended diagnostic testing
to confirm positive cell-free DNA tests, and that management
decisions not be based solely on
the results of cell-free DNA testing. ACOG further recommends
that patients with indeterminate
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or uninterpretable (ie, no call) cell-free DNA test results be
referred for genetic counseling and
offered ultrasound evaluation and diagnostic testing because no
call findings have been
associated with an increased risk of aneuploidy.
As noted in the 2015 ACOG committee opinion, cell-free DNA
screening does not assess the risk
of anomalies such as neural tube defects. Patients should
continue to be offered ultrasound or
maternal serum alpha-fetoprotein screening, regardless of the
type of serum screening selected.
In some cases, tissue samples from chorionic villous sampling
(CVS) or amniocentesis may be
insufficient for karyotyping; confirmation by specific
fluorescent in situ hybridization (FISH) assay
is acceptable for these samples.
Evidence Review
Background
Fetal Aneuploidy
Fetal chromosomal abnormalities occur in approximately 1 in 160
live births. Most fetal
chromosomal abnormalities are aneuploidies, defined as an
abnormal number of chromosomes.
The trisomy syndromes are aneuploidies involving 3 copies of one
chromosome. The most
important risk factor for trisomy syndromes is maternal age. The
approximate risk of a trisomy
21 (T21; Down syndrome)affected birth is 1 in 1100 at age 25 to
29. The risk of a fetus with T21
(at 16 weeks of gestation) is about 1 in 250 at age 35 and 1 in
75 at age 40.1
T21 is the most common cause of human birth defects and provides
the impetus for current
maternal serum screening programs. Other trisomy syndromes
include T18 (Edwards syndrome)
and T13 (Patau syndrome), which are the next most common forms
of fetal aneuploidy,
although the percentage of cases surviving to birth is low and
survival beyond birth is limited.
The prevalence of these other aneuploidies is much lower than
the prevalence of T21, and
identifying them is not currently the main intent of prenatal
screening programs. Also, the
clinical implications of identifying T18 and 1T3 are unclear,
because survival beyond birth is
limited for both conditions.
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Fetal Aneuploidy Screening
Current national guidelines recommend that all pregnant women be
offered screening for fetal
aneuploidy (referring specifically to T21, T18, and T13) before
20 weeks of gestation, regardless
of age.2 Standard aneuploidy screening involves combinations of
maternal serum markers and
fetal ultrasound done at various stages of pregnancy. The
detection rate for various
combinations of noninvasive testing ranges from 60% to 96% when
the false-positive rate is set
at 5%. When tests indicate a high risk of a trisomy syndrome,
direct karyotyping of fetal tissue
obtained by amniocentesis or chorionic villous sampling (CVS) is
required to confirm that T21 or
another trisomy is present. Both amniocentesis and CVS are
invasive procedures and have an
associated risk of miscarriage. A new screening strategy that
reduces unnecessary amniocentesis
and CVS procedures and increases detection of T21, T18, and T13
could improve outcomes.
Confirmation of positive noninvasive screening tests with
amniocentesis or CVS is
recommended; with more accurate tests, fewer women would receive
positive screening results.
Commercial, noninvasive, sequencing-based testing of maternal
serum for fetal trisomy
syndromes is now available. The test technology involves
detection of fetal cell-free DNA
fragments present in the plasma of pregnant women. As early as 8
to 10 weeks of gestation,
these fetal DNA fragments comprise 6% to 10% or more of the
total cell-free DNA in a maternal
plasma sample. The tests are unable to provide a result if the
fetal fraction is too low, that is,
below about 4%. Fetal fraction can be affected by maternal and
fetal characteristics. For
example, fetal fraction was found to be lower at higher maternal
weights and higher with
increasing fetal crown-rump length.
Cell-Free Fetal DNA Analysis Methods
Sequencing-based tests use 1 of 2 general approaches to
analyzing cell-free DNA. The first
category of tests uses quantitative or counting methods. The
most widely used technique to
date uses massively parallel sequencing (MPS; also known as
next-generation or next gen
sequencing). DNA fragments are amplified by polymerase chain
reaction; during the sequencing
process, the amplified fragments are spatially segregated and
sequenced simultaneously in a
massively parallel fashion. Sequenced fragments can be mapped to
the reference human
genome to obtain numbers of fragment counts per chromosome. The
sequencing-derived
percent of fragments from the chromosome of interest reflects
the chromosomal representation
of the maternal and fetal DNA fragments in the original maternal
plasma sample. Another
technique is direct DNA analysis, which analyzes specific
cell-free DNA fragments across samples
and requires approximately a tenth the number of cell-free DNA
fragments as MPS. The digital
analysis of selected regions (DANSR) is an assay that uses
direct DNA analysis.
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The second general approach is single nucleotide polymorphism
(SNP)-based methods. These
use targeted amplification and analysis of approximately 20,000
SNPs on selected chromosomes
(eg, 21, 18, 13) in a single reaction. A statistical algorithm
is used to determine the number of
each type of chromosome.
At least some of the commercially available cell-free fetal DNA
prenatal tests also test for other
abnormalities including sex chromosome abnormalities and
selected microdeletions. Sex
chromosome aneuploidies (eg, 45,X [Turner syndrome]; 47,XXY,
47,XYY) occur in approximately
1 in 400 live births. These aneuploidies are typically diagnosed
postnatally, sometimes not until
adulthood, such as during an evaluation of diminished fertility.
Alternatively, sex chromosome
aneuploidies may be diagnosed incidentally during invasive
karyotype testing of pregnant
women at high risk for Down syndrome. Potential benefits of
early identification (eg, the
opportunity for early management of the manifestations of the
condition) must be balanced
against potential harms that can include stigmatization and
distortion of a familys view of the
child.
Copy Number Variants and Clinical Disorders
Microdeletions (also known as submicroscopic deletions) are
defined as chromosomal deletions
that are too small to be detected by microscopy or conventional
cytogenetic methods. They can
be as small as 1 and 3 megabases (Mb) long. Microdeletions,
along with microduplications, are
collectively known as copy number variations (CNVs). CNVs can
lead to disease when the
change in copy number of a dose-sensitive gene or genes disrupts
the ability of the gene/s to
function and effects the amount of protein produced. A number of
genomic disorders
associated with microdeletion have been identified. The
disorders have distinctive and, in many
cases, serious clinical features, such as cardiac anomalies,
immune deficiency, palatal defects,
and developmental delay as in DiGeorge syndrome. Some of the
syndromes such as DiGeorge
have complete penetrance yet marked variability in clinical
expressivity. Reasons for the variable
clinical expressivity are not entirely clear. A contributing
factor is that the breakpoints of the
microdeletions may vary, and there may be a correlation between
the number of haplo-
insufficient genes and phenotypic severity.
Fetal Detection of CNVs
A proportion of microdeletions are inherited and some are de
novo. Accurate estimates of the
prevalence of microdeletion syndromes during pregnancy or at
birth are not available. Risk of a
fetus with a microdeletion syndrome is independent of maternal
age. There is little population-
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based data and most studies published to date base estimates on
phenotypic presentation. The
22q11.2 (DiGeorge) deletion is the most common microdeletion
associated with a clinical
syndrome. According to the GeneTests database, current estimates
of prevalence range from 1
in 4000 to 1 in 6395 live births.3 Prevalence estimates for
other microdeletions are between 1 in
5000 and 1 in 10,000 live births for 1p36 deletion syndrome,
between 1 in 10,000 and 1 in
30,000 for Prader-Willi syndrome, and between 1 in 12,000 and 1
in 24,000 for Angelman
syndrome. The above figures likely underestimate the prevalence
of these microdeletion
syndromes in the prenatal population because the population of
mutation carriers includes
phenotypically normal or very mildly affected individuals.
Routine prenatal screening for microdeletion syndromes is not
recommended by national
organizations. Current practice is to offer invasive prenatal
diagnostic testing in selected cases
to women when a prenatal ultrasound indicates anomalies (eg,
heart defects, cleft palate) that
could be associated with a particular microdeletion syndrome.
Samples are analyzed using
fluorescence in situ hybridization (FISH), chromosomal
microarray analysis (CMA), or
karyotyping. In addition, families at risk (eg, those known to
have the deletion or with a previous
affected child) generally receive genetic counseling and those
who conceive naturally may
choose prenatal diagnostic testing. Most affected individuals,
though, are identified postnatally
based on clinical presentation and may be confirmed by genetic
testing. Using 22q11.2 deletion
syndrome as an example, although clinical characteristics vary,
palatal abnormalities (eg, cleft
palate) occur in approximately 69% of individuals, congenital
heart disease in 74%, and
characteristic facial features are present in a majority of
individuals of northern European
heritage.
Summary of Evidence
For individuals who have a singleton pregnancy who receive NIPS
for T21 using cell-free fetal
DNA, the evidence includes observational studies and systematic
reviews. Relevant outcomes
are test accuracy and validity, morbid events, and resource
utilization. Published studies on
commercially available tests and meta-analyses of these studies
have consistently demonstrated
very high sensitivity and specificity for detecting Down
syndrome (T21) in singleton pregnancies.
Most studies included only women at high risk of T21, but
several studies, including one with a
large sample size, have reported similar levels of diagnostic
accuracy in average-risk women.
Compared with standard serum screening, both the sensitivity and
specificity of cell-free fetal
DNA screening are considerably higher. As a result, screening
with cell-free fetal DNA will result
in fewer missed cases of Down syndrome, fewer invasive
procedures, and fewer cases of
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pregnancy loss following invasive procedures. The evidence is
sufficient to determine that the
technology results in a meaningful improvement in the net health
outcome.
For individuals who have a singleton pregnancy who receive NIPS
for T18, T13, or sex
chromosome aneuploidies using cell-free fetal DNA, the evidence
includes observational
studies, mainly in high-risk pregnancies, and systematic
reviews. Relevant outcomes are test
accuracy and validity, morbid events, and resource utilization.
Meta-analyses of available data
have suggested high sensitivities and specificities, but the
small number of cases, especially for
T13, makes definitive conclusions difficult. The evidence is
insufficient to determine the effects
of the technology on health outcomes.
For individuals who have twin or multiple pregnancies who
receive NIPS for aneuploidies using
cell-free fetal DNA, the evidence includes several observational
studies and a systematic review.
Relevant outcomes are test accuracy and validity, morbid events,
and resource utilization. The
total number of cases of aneuploidy identified in these studies
is small and is insufficient to draw
conclusions about clinical validity. There is a lack of direct
evidence of clinical utility, and a chain
of evidence cannot be conducted due to insufficient evidence on
clinical validity. The evidence is
insufficient to determine the effects of the technology on
health outcomes.
For individuals with pregnancy(ies) who receive NIPS for
microdeletions using cell-free fetal
DNA, the evidence includes several observational studies.
Relevant outcomes are test accuracy
and validity, morbid events, and resource utilization. The
available studies on clinical validity
have limitations (eg, missing data on confirmatory testing,
false-negatives), and the added
benefit of NIPS compared with current approaches is unclear.
Moreover, the clinical utility of
NIPS for microdeletions remains unclear and has not been
evaluated in published studies. The
evidence is insufficient to determine the effects of the
technology on health outcomes.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this
policy are listed in Table 1.
Table 1. Summary of Key Trials
NCT No. Trial Name Planned
Enrollme
nt
Completio
n Date
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NCT No. Trial Name Planned
Enrollme
nt
Completio
n Date
Ongoing
NCT01545674a
Prenatal Non-invasive Aneuploidy Test Utilizing SNPs Trial
(PreNATUS)
1000 Dec 2017
NCT01925742 PEGASUS: PErsonalized Genomics for Prenatal
Aneuploidy
Screening Using Maternal Blood
5600 Dec 2017
NCT: national clinical trial. a Denotes industry-sponsored or
cosponsored trial.
Clinical Input Received from Physician Specialty Societies and
Academic
Medical Centers
While the various physician specialty societies and academic
medical centers may provide
appropriate reviewers who collaborate with and make
recommendations during this process,
input received does not represent an endorsement or position
statement by the physician
specialty societies or academic medical centers, unless
otherwise noted.
In response to requests, input was received from 3 physician
specialty societies and 4 academic
medical centers while this policy was under review in 2012.
There was a consensus that
sequencing-based tests to determine trisomy 21 (T21) from
maternal plasma cell-free fetal DNA
may be considered medically necessary in women with high-risk
singleton pregnancies
undergoing screening for T21. Input was mixed on whether
sequencing-based tests to
determine T21 from maternal plasma DNA may be considered
medically necessary in women
with average-risk singleton pregnancies. An American College of
Obstetricians and
Gynecologists (ACOG) genetics committee opinion, included as
part of the specialty societys
input, did not recommend the new tests at this time for women
with singleton pregnancies who
were not at high risk of aneuploidy. There was a consensus that
sequencing-based tests to
determine T21 from maternal plasma DNA are investigational for
women with multiple
pregnancies. Regarding an appropriate protocol for using
sequencing-based testing, there was a
consensus that testing should not be used as a single-screening
test without confirmation of
results by karyotyping. There was mixed input on the use of the
test as a replacement for
standard screening tests with karyotyping confirmation and on
use as a secondary screen in
women with screen positive on standard screening tests with
karyotyping confirmation. Among
the 5 reviewers who responded to the questions (which did not
include ACOG), there was a
consensus that the modeling approach is sufficient to determine
the clinical utility of the new
https://www.clinicaltrials.gov/ct2/show/NCT01545674?term=NCT01545674&rank=1https://www.clinicaltrials.gov/ct2/show/NCT01925742?term=NCT01925742&rank=1
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tests and near-consensus that there is no need for clinical
trials comparing a screening protocol
using the new tests to a screening protocol using standard serum
screening before initiation of
clinical use of the tests.
Practice Guidelines and Position Statements
American College of Obstetricians and Gynecologists and Society
for
Maternal-Fetal Medicine
In 2015, the American College of Obstetricians and Gynecologists
(ACOG) and the Society for
Maternal-Fetal Medicine (SMFM) updated its joint committee
opinion on noninvasive testing for
fetal aneuploidy (No. 640).32 The complete list of
recommendations in the 2015 committee
opinion follows:
A discussion of the risks, benefits, and alternatives of various
methods of prenatal screening
and diagnostic testing, including the option of no testing,
should occur with all patients.
Given the performance of conventional screening methods, the
limitations of cell-free DNA
screening performance, and the limited data on
cost-effectiveness in the low-risk obstetric
population, conventional screening methods remain the most
appropriate choice for first-
line screening for most women in the general obstetric
population.
Although any patient may choose cell-free DNA analysis as a
screening strategy for common
aneuploidies regardless of her risk status, the patient choosing
this testing should
understand the limitations and benefits of this screening
paradigm in the context of
alternative screening and diagnostic options.
The cell-free DNA test will screen for only the common trisomies
and, if requested, sex
chromosome composition.
Given the potential for inaccurate results and to understand the
type of trisomy for
recurrence-risk counseling, a diagnostic test should be
recommended for a patient who has
a positive cell-free DNA test result.
Parallel or simultaneous testing with multiple screening
methodologies for aneuploidy is not
cost-effective and should not be performed.
Management decisions, including termination of the pregnancy,
should not be based on the
results of the cell-free DNA screening alone.
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Women whose results are not reported, indeterminate, or
uninterpretable (a no call test
result) from cell-free DNA screening should receive further
genetic counseling and be
offered comprehensive ultrasound evaluation and diagnostic
testing because of an increased
risk of aneuploidy.
Routine cell-free DNA screening for microdeletion syndromes
should not be performed.
Cell-free DNA screening is not recommended for women with
multiple gestations.
If a fetal structural anomaly is identified on ultrasound
examination, diagnostic testing
should be offered rather than cell-free DNA screening.
Patients should be counseled that a negative cell-free DNA test
result does not ensure an
unaffected pregnancy.
Cell-free DNA screening does not assess risk of fetal anomalies
such as neural tube defects
or ventral wall defects; patients who are undergoing cell-free
DNA screening should be
offered maternal serum alpha-fetoprotein screening or ultrasound
evaluation for risk
assessment.
Patients may decline all screening or diagnostic testing for
aneuploidy.
In December 2015, SMFM published a special report clarifying its
recommendations on cell-free
DNA screening, as follows33:
The purpose of this statement is to clarify that SMFM does not
recommend that cfDNA [cell-
free DNA] aneuploidy screening be offered to all pregnant women,
nor does it suggest a
requirement for insurance coverage for cfDNA screening in women
at low risk of aneuploidy.
However, SMFM believes, due to the ethics of patient autonomy,
that the option should be
available to women who request additional testing beyond what is
currently recommended
by professional societies. SMFM recognizes the value of cfDNA
screening for women at
higher risk for aneuploidy but considers that cfDNA screening is
not the appropriate choice
for first-line screening for the low-risk obstetric population
at the present time. For this
population, conventional screening methods remain the preferred
approach....
In May, 2016, ACOG and SMFM released a practice bulletin summary
(No. 163) on screening for
fetal aneuploidy.34 The following recommendations cell-free DNA
are based on good and
consistent scientific evidence:
Women who have a negative screening test result should not be
offered additional
screening tests for aneuploidy because this will increase their
potential for a false-positive
test result.
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Because cell-free DNA is a screening test with the potential for
false-positive and false-
negative results, such testing should not be used as a
substitute for diagnostic testing.
All women with a positive cell-free DNA test result should have
a diagnostic procedure
before any irreversible action, such as pregnancy termination,
is taken.
Women whose cell-free DNA screening test results are not
reported, are indeterminate, or
are uninterpretable (a no call test result) should receive
further genetic counseling and be
offered comprehensive ultrasound evaluation and diagnostic
testing because of an increased
risk of aneuploidy.
The following recommendations are based on limited or
inconsistent scientific evidence:
Cell-free DNA screening tests for microdeletions have not been
validated clinically and are
not recommended at this time.
No method of aneuploidy screening is as accurate in twin
gestations as it is in singleton
pregnancies. Because data generally are unavailable for
higher-order multifetal gestations,
analyte screening for fetal aneuploidy should be limited to
singleton and twin pregnancies.
The following recommendations are based primarily on based
primarily on consensus and
expert opinion:
Some women who receive a positive test result from traditional
screening may prefer to
have cell-free DNA screening rather than undergo definitive
testing.
This approach may delay definitive diagnosis and management and
may fail to identify some
fetuses with aneuploidy.
Parallel or simultaneous testing with multiple screening
methodologies for aneuploidy is not
cost effective and should not be performed.
European Society of Human Genetics and American Society of
Human
Genetics
In 2015, the public and professional policy committee of the
European Society of Human
Genetics and the social issues committee of the American Society
of Human Genetics issued a
joint statement on NIPS (also called noninvasive prenatal
testing [NIPT]).35 Relevant
recommendations are as follows:
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NIPT offers improved accuracy when testing for common autosomal
aneuploidies compared
with existing tests such as cTFS (combined first-trimester
screening). However, a positive
NIPT result should not be regarded as a final diagnosis: false
positives occur for a variety of
reasons (including that the DNA sequenced is both maternal and
fetal in origin, and that the
fetal fraction derives from the placenta as well as the
developing fetus). Thus, women should
be advised to have a positive result confirmed through
diagnostic testing, preferably by
amniocentesis, if they are considering a possible termination of
pregnancy.
The better test performance, including lower invasive testing
rate of NIPT-based screening
should not lead to lower standards for pretest information and
counseling. This is especially
important in the light of the aim of providing pregnant women
with meaningful options for
reproductive choice. There should be specific attention paid to
the information needs of
women from other linguistic and cultural backgrounds or who are
less health literate.
If NIPT is offered for a specific set of conditions (eg,
trisomies 21, 18 and 13), it may not be
reasonably possible to avoid additional findings, such as other
chromosomal anomalies or
large scale insertions or deletions. As part of pretest
information, women and couples should
be made aware of the possibility of such additional findings and
the range of their
implications. There should be a clear policy for dealing with
such findings, as much as
possible also taking account of pregnant womens wishes with
regard to receiving or not
receiving specific information.
Expanding NIPT-based prenatal screening to also report on sex
chromosomal abnormalities
and microdeletions not only raises ethical concerns related to
information and counseling
challenges but also risks reversing the important reduction in
invasive testing achieved with
implementation of NIPT for aneuploidy, and is therefore
currently not recommended.
National Society of Genetic Counselors
In 2013, the National Society of Genetic Counselors (NSGC)
published a position statement on
NIPS of cell-free DNA in maternal plasma.36 NSGC supports
noninvasive cell-free DNA testing as
an option in women who want testing for aneuploidy. The document
states that the test has
been primarily validated in pregnancies considered to be at
increased risk of aneuploidy, and
the organization does not support routine first-tier screening
in low-risk populations. In
addition, the document states that test results should not be
considered diagnostic, and
abnormal findings should be confirmed through conventional
diagnostic procedures, such as
chronic villous sampling (CVS) and amniocentesis.
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American College of Medical Genetics and Genomics
In 2016, the American College of Medical Genetics and Genomics
(ACMG) published a position
statement on noninvasive prenatal screening (NIPS) for fetal
aneuploidy.37 Relevant
recommendations are as follows. ACMG recommends:
Informing all pregnant women that NIPS is the most sensitive
screening option for
traditionally screened aneuploidies (ie, Patau, Edwards, and
Down syndromes).
Referring patients to a trained genetics professional when an
increased risk of aneuploidy is
reported after NIPS.
Offering diagnostic testing when a positive screening test
result is reported after NIPS.
Providing accurate, balanced, up-to-date information, at an
appropriate literacy level when a
fetus is diagnosed with a chromosomal or genomic variation in an
effort to educate
prospective parents about the condition of concern. These
materials should reflect the
medical and psychosocial implications of the diagnosis.
ACMG does not recommend:
NIPS to screen for autosomal aneuploidies other than those
involving chromosomes 13, 18,
and 21.
International Society for Prenatal Diagnosis
In 2015, the International Society for Prenatal Diagnosis
published a position statement on
prenatal diagnosis of chromosomal abnormalities, an update of
their 2013 statement.38,39 (Note
that a number of the authors of the 2015 report had financial
links to the industry.) Following is
the summary of recommendations:
I. High sensitivities and specificities are potentially
achievable with cfDNA [cell-free DNA]
screening for some fetal aneuploidies, notably trisomy 21.
II. Definitive diagnosis of Down syndrome and other fetal
chromosome abnormalities can
only be achieved through testing on cells obtained by
amniocentesis or CVS.
III. The use of maternal age alone to assess fetal Down syndrome
risk in pregnant women is
not recommended.
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IV. A combination of ultrasound NT measurement and maternal
serum markers in the first
trimester should be available to women who want an early risk
assessment and for whom
cfDNA screening cannot be provided.
V. A four-marker serum test should be available to women who
first attend for their
prenatal care after 13 weeks 6 days of pregnancy and where cfDNA
screening cannot be
provided.
VI. Protocols that combine first trimester and second trimester
conventional markers are
valid.
VII. Second trimester ultrasound can be a useful adjunct to
conventional aneuploidy
screening protocols.
VIII. When cfDNA screening is extended to microdeletion and
microduplication syndromes or
rare trisomies the testing should be limited to clinically
significant disorders or well
defined severe conditions. There should be defined estimates for
the detection rates,
false-positive rates, and information about the clinical
significance of a positive test for
each disorder being screened.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (USPSTF) does not
currently address screening for Down
syndrome. This topic was addressed in the 1990s; it is no longer
listed on the USPSTF website.
Medicare National Coverage
There is no national coverage determination (NCD). In the
absence of an NCD, coverage
decisions are left to the discretion of local Medicare
carriers.
Regulatory Status
Clinical laboratories may develop and validate tests in-house
and market them as a laboratory
service; laboratory-developed tests must meet the general
regulatory standards of the Clinical
Laboratory Improvement Act. Laboratories that offer
laboratory-developed tests must be
licensed by the Clinical Laboratory Improvement Act for
high-complexity testing. To date, the
-
Page | 16 of 23
U.S. Food and Drug Administration has chosen not to require any
regulatory review of
noninvasive prenatal screening tests using cell-free fetal DNA.
Commercially available tests
include but are not limited to the following:
VisibiliT (Sequenom Laboratories, now LabCorp) tests for T21 and
T18, and tests for fetal
gender.
MaterniT21 PLUS (Sequenom Laboratories) core test includes T21,
T18, and T13 and fetal
sex aneuploidies. The enhanced sequencing series includes
testing for T16 and T22 and 7
microdeletions: 22q deletion syndrome (DiGeorge syndrome), 5p
(cri du chat syndrome), 15q
(Prader-Willi and Angelman syndromes), 1p36 deletion syndrome,
4p (Wolf-Hirschhorn
syndrome), 8q (Langer-Giedion syndrome), and 11q (Jacobsen
syndrome). The test uses MPS
and reports results as positive or negative. The enhanced
sequencing series is offered on an
opt-out basis.
Harmony (Ariosa Diagnostics, now Roche) tests for T21, T18, and
T13. The test uses
directed DNA analysis and results are reported as a risk
score.
Panorama (Natera) is a prenatal test for detecting T21, T18, and
T13, as well as select sex
chromosome abnormalities. It uses single-nucleotide variant
technology; results are reported
as a risk score. An extended panel tests for 5 microdeletions:
22q deletion syndrome
(DiGeorge syndrome), 5p (cri du chat syndrome), 15q11-13
(Prader-Willi and Angelman
syndromes), and 1p36 deletion syndrome. Screening for 22q11.2
will be included in the
panel unless the opt-out option is selected; screening for the
remaining 4 microdeletions is
offered on an opt-in basis.
Verifi (Verinata Health, now Illumina) is a prenatal test for
T21, T18, and T13. The test uses
MPS and calculates a normalized chromosomal value, reporting
results as one of three
categories: no aneuploidy detected, aneuploidy detected, or
aneuploidy suspected.
InformaSeqSM (Integrated Genetics) is a prenatal test for
detecting T21, T18, and T13, with
optional additional testing for select sex chromosome
abnormalities. It uses the Illumina
platform and reports results in similar manner.
QNatal Advanced (Quest Diagnostics) tests for T21, T18, and
T13.
References
-
Page | 17 of 23
1. Hook EB, Cross PK, Schreinemachers DM. Chromosomal
abnormality rates at amniocentesis and in live-born infants. JAMA.
Apr
15 1983;249(15):2034-2038. PMID 6220164
2. American College of Obstetricians and Gynecologists (ACOG).
Practice Bulletin No. 77: screening for fetal chromosomal
abnormalities. Obstet Gynecol. Jan 2007;109(1):217-227. PMID
17197615
3. McDonald-McGinn DM, Emanuel BE, Zacka EH. 22q11.2 Deletion
Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds.
GeneReviews. Seattle, WA: University of Washington; 2013.
4. Blue Cross Blue Shield Association Technology Evaluation
Center (TEC). Sequencing-based tests to determine fetal down
syndrome (trisomy 21) from maternal plasma DNA. TEC Assessment
Program. 2013;Volume 27:Tab 10.
5. Blue Cross Blue Shield Association Technology Evaluation
Center (TEC). Noninvasive prenatal cell-free fetal DNA-based
screening for aneuploides other than trisomy 21. TEC Assessment
Program. 2014;Volume 29:Tab 7.
6. Food and Drug Adminstration (FDA). Ultra High Throughput
Sequencing for Clinical Diagnostic Applications - Approaches to
Assess Analytical Validity, June 23, 2011 (Archived
Content).
https://www.federalregister.gov/documents/2011/05/19/2011-12310/ultra-high-throughput-sequencing-for-clinical-
diagnostic-applications-approaches-to-assess Accessed September
2017.
7. Mackie FL, Hemming K, Allen S, et al. The accuracy of
cell-free fetal DNA-based non-invasive prenatal testing in
singleton
pregnancies: a systematic review and bivariate meta-analysis.
BJOG. Jan 2017;124(1):32-46. PMID 27245374
8. Taylor-Phillips S, Freeman K, Geppert J, et al. Accuracy of
non-invasive prenatal testing using cell-free DNA for detection
of
Down, Edwards and Patau syndromes: a systematic review and
meta-analysis. BMJ Open. Jan 18 2016;6(1):e010002. PMID
26781507
9. Gil MM, Akolekar R, Quezada MS, et al. Analysis of cell-free
DNA in maternal blood in screening for aneuploidies:
meta-analysis.
Fetal Diagn Ther. Feb 8 2014;35(3):156-173. PMID 24513694
10. Iwarsson E, Jacobsson B, Dagerhamn J, et al. Analysis of
cell-free fetal DNA in maternal blood for detection of trisomy 21,
18
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population - a systematic review and meta-analysis. Acta Obstet
Gynecol Scand. Jan 2017;96(1):7-18. PMID 27779757
11. Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of
maternal plasma reliably identifies trisomy 18 and trisomy 13 as
well
as Down syndrome: an international collaborative study. Genet
Med. Mar 2012;14(3):296-305. PMID 22281937
12. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA
sequencing of maternal plasma to detect Down syndrome: an
international clinical validation study. Genet Med. Nov
2011;13(11):913-920. PMID 22005709
13. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive
detection of fetal trisomy 21 by sequencing of DNA in maternal
blood: a
study in a clinical setting. Am J Obstet Gynecol. Mar
2011;204(3):205 e201-211. PMID 21310373
14. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal
aneuploidy detection by maternal plasma DNA sequencing. Obstet
Gynecol. May 2012;119(5):890-901. PMID 22362253
15. Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of
fetal chromosomal abnormalities by massively parallel DNA
sequencing of cell-free fetal DNA from maternal blood. Clin
Chem. Jul 2011;57(7):1042-1049. PMID 21519036
16. Norton ME, Brar H, Weiss J, et al. Non-Invasive Chromosomal
Evaluation (NICE) Study: results of a multicenter prospective
cohort study for detection of fetal trisomy 21 and trisomy 18.
Am J Obstet Gynecol. Aug 2012;207(2):137 e131-138. PMID
22742782
17. Ashoor G, Syngelaki A, Wagner M, et al. Chromosome-selective
sequencing of maternal plasma cell-free DNA for first-trimester
detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol. Apr
2012;206(4):322 e321-325. PMID 22464073
18. Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal
detection and selective analysis of cell-free DNA obtained from
maternal blood: evaluation for trisomy 21 and trisomy 18. Am J
Obstet Gynecol. Apr 2012;206(4):319 e311-319. PMID 22464072
19. Nicolaides KH, Syngelaki A, Gil M, et al. Validation of
targeted sequencing of single-nucleotide polymorphisms for
non-invasive
prenatal detection of aneuploidy of chromosomes 13, 18, 21, X,
and Y. Prenat Diagn. Jun 2013;33(6):575-579. PMID 23613152
https://www.federalregister.gov/documents/2011/05/19/2011-12310/ultra-high-throughput-sequencing-for-clinical-diagnostic-applications-approaches-to-assesshttps://www.federalregister.gov/documents/2011/05/19/2011-12310/ultra-high-throughput-sequencing-for-clinical-diagnostic-applications-approaches-to-assess
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20. Porreco RP, Garite TJ, Maurel K, et al. Noninvasive prenatal
screening for fetal trisomies 21, 18, 13 and the common sex
chromosome aneuploidies from maternal blood using massively
parallel genomic sequencing of DNA. Am J Obstet Gynecol.
Oct 2014;211(4):365 e361-312. PMID 24657131
21. Norton ME, Baer RJ, Wapner RJ, et al. Cell-free DNA vs
sequential screening for the detection of fetal chromosomal
abnormalities. Am J Obstet Gynecol. Jun 2016;214(6):727
e721-726. PMID 26709085
22. Zhang H, Gao Y, Jiang F, et al. Non-invasive prenatal
testing for trisomies 21, 18 and 13: clinical experience from
146,958
pregnancies. Ultrasound Obstet Gynecol. May 2015;45(5):530-538.
PMID 25598039
23. Garfield SS, Armstrong SO. Clinical and cost consequences of
incorporating a novel non-invasive prenatal test into the
diagnostic pathway for fetal trisomies. J Managed Care Med.
2012;15(2):34-41.
24. Ohno M, Caughey A. The role of noninvasive prenatal testing
as a diagnostic versus a screening tool--a cost-effectiveness
analysis. Prenat Diagn. Jul 2013;33(7):630-635. PMID
23674316
25. Gil MM, Accurti V, Santacruz B, et al. Analysis of cell-free
DNA in maternal blood in screening for aneuploidies: updated
meta-
analysis. Ultrasound Obstet Gynecol. Apr 11 2017. PMID
28397325
26. Du E, Feng C, Cao Y, et al. Massively parallel sequencing
(MPS) of cell-free fetal DNA (cffDNA) for trisomies 21, 18, and 13
in
twin pregnancies. Twin Res Hum Genet. Jun 2017;20(3):242-249.
PMID 28485265
27. Fosler L, Winters P, Jones KW, et al. Aneuploidy screening
by non-invasive prenatal testing in twin pregnancy. Ultrasound
Obstet Gynecol. Apr 2017;49(4):470-477. PMID 27194226
28. Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of
noninvasive prenatal testing: detection of fetal microdeletion
syndromes. Am J Obstet Gynecol. Mar 2015;212(3):332 e331-339.
PMID 25479548
29. Gross SJ, Stosic M, McDonald-McGinn DM, et al. Clinical
experience with single-nucleotide polymorphism-based
non-invasive
prenatal screening for 22q11.2 deletion syndrome. Ultrasound
Obstet Gynecol. Feb 2016;47(2):177-183. PMID 26396068
30. Helgeson J, Wardrop J, Boomer T, et al. Clinical outcome of
subchromosomal events detected by whole-genome noninvasive
prenatal testing. Prenat Diagn. Oct 2015;35(10):999-1004. PMID
26088833
31. Zhao C, Tynan J, Ehrich M, et al. Detection of fetal
subchromosomal abnormalities by sequencing circulating cell-free
DNA from
maternal plasma. Clin Chem. Apr 2015;61(4):608-616. PMID
25710461
32. Committee Opinion No. 640: Cell-free DNA Screening for Fetal
Aneuploidy. Obstet Gynecol. Jun 29 2015. PMID 26114726
33. Society for Maternal-Fetal Medicine Publications Committee.
Electronic address eso. SMFM Statement: clarification of
recommendations regarding cell-free DNA aneuploidy screening. Am
J Obstet Gynecol. Dec 2015;213(6):753-754. PMID
26458766
34. Practice Bulletin No. 163 Summary: Screening for Fetal
Aneuploidy. Obstet Gynecol. May 2016;127(5):979-981. PMID
27101120
35. Dondorp W, de Wert G, Bombard Y, et al. Non-invasive
prenatal testing for aneuploidy and beyond: challenges of
responsible
innovation in prenatal screening. Eur J Hum Genet. Oct
2015;23(11):1438-1450. PMID 25782669
36. Devers PL, Cronister A, Ormond KE, et al. Noninvasive
prenatal testing/noninvasive prenatal diagnosis: the position of
the
National Society of Genetic Counselors. J Genet Couns. Jun
2013;22(3):291-295. PMID 23334531
37. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive
prenatal screening for fetal aneuploidy, 2016 update: a
position
statement of the American College of Medical Genetics and
Genomics. Genet Med. Oct 2016;18(10):1056-1065. PMID 27467454
38. Benn P, Borrell A, Chiu RW, et al. Position statement from
the Chromosome Abnormality Screening Committee on behalf of the
Board of the International Society for Prenatal Diagnosis.
Prenat Diagn. Aug 2015;35(8):725-734. PMID 25970088
39. Benn P, Borell A, Chiu R, et al. Position statement from the
Aneuploidy Screening Committee on behalf of the Board of the
International Society for Prenatal Diagnosis. Prenat Diagn. Jul
2013;33(7):622-629. PMID 23616385
40. Nicolaides KH, Syngelaki A, Ashoor G, et al. Noninvasive
prenatal testing for fetal trisomies in a routinely screened
first-
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e371-376. PMID 23107079
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Page | 19 of 23
41. Pergament E, Cuckle H, Zimmermann B, et al.
Single-nucleotide polymorphism-based noninvasive prenatal screening
in a high-
risk and low-risk cohort. Obstet Gynecol. Aug 2014;124(2 Pt
1):210-218. PMID 25004354
Appendix
Appendix Table 1: Aneuploidy Detection by Sequencing in
High-Risk
Singleton Pregnancies: Test Performance
Studya N, Final
Analysisb
Indeterminate
Samples
Sensitivity, % (95% CI) Specificity, % (95%
CI)
T21 T13 T18 T21 T13 T18
Sequenom (MaterniT21)
Porreco
(2014)20
Total
N=3430
T21: n=137
T18: n=39
T13: n=13
54/3430
Insufficient quality
criteria
100
(97.3 to
100)
87.5 (61.6
to 98.5)
92.3
(79.1 to
98.4)
99.9 (99.7
to 99.98)
100
(98.89
to
100)
100
(99.89
to 98.4)
Palomaki
(2012)11
Total
N=1971
T21: n=212
T18: n=59
T13: n=12
17/1988 (0.9%)
Test failure including
fetal fraction QC
99.1
(96.6 to
99.9)
91.7 (61.5
to 99.8)
100
(93.9 to
100)
99.9 (99.7
to 99.9)
99.1
(98.5
to
99.5)
99.7
(99.3 to
99.9)
Ehrich
(2011)13
Total N=449
T21: n=39
18/467 (3.8%)
Failed test QC,
including fetal
fraction
100
(91.0 to
100)
99.7 (98.6
to 99.9)
Illumina (Verifi)
Bianchi
(2012)14
Total
N=516d
T21: n=89
T18: n=36
T13: n=14
16/532 (3%)
Low fetal DNA
100
(95.9 to
100)
78.6 (49.2
to -95.3)
97.2
(85.5 to
99.9)
100 (99.1
to 100)
100
(99.2
to
100)
100
(99.2 to
100)
Sehnert Total test 1/47 (2%) 100
(75.3 to
100
(63.1 to
100 (89.7 100
(91.0 to
-
Page | 20 of 23
Studya N, Final
Analysisb
Indeterminate
Samples
Sensitivity, % (95% CI) Specificity, % (95%
CI)
(2011)15
set=46
T21: n=13
T18: n=8
T13: n=1
T13 classified as no
call
100) 100) to 100) 100)
Ariosa (Harmony)
Norton
(2012)16
Total
N=3080
T21: n=81
T18: n=38
(73 = other
based on
invasive
testing)
57/3228 (1.8%)
Low fetal DNA
91/3228 (2.8%)
Test failure
total (4.6%)
100
(95.5 to
100)
97.4
(86.2 to
99.9)
99.97
(99.8 to
99.9)
99.93
(99.7 to
99.9)
Ashoor
(2012)17
Total N=397
T21: n=50
T18: n=50
3/400 (0.75%)
Test failure
100
(92.9 to
100)
98 (89.4
to 99.9)
100 (98.8
to 100)
100
(98.8 to
100)
Sparks
(2012)18
Validation
set
Total N=167
T21: n=36
T18: n=8
N=0
No failures in test
set
100
(90.3 to
100)
100
(63.1 to
100)
100 (97.0
to 100)
100
(97.0 to
100)
Natera (Panorama)
Nicholaid
es
(2013)19
Total N=242
T21: n=25
T18: n=3
T13: n=1
13/242 (5.4%)
Failed internal
quality control
100
(86.3 to
100)
100 (98.2
to 100)
CI: confidence interval; T13: trisomy 13; T18: trisomy 18; T21:
trisomy 21. a Other than Ashoor (2012) and Nicolaides (2013), all
studies had industry-funding and additionally, at least some
authors were company employees and/or shareholders. b After
indeterminate samples removed.
c Results for T21 were abstracted from Palomaki (2012), rather
than Palomaki (2011), because of data corrections for
GC content and use of repeat masking, part of the current test
procedure. d Patients with complex karyotypes were excluded from
the analysis.
-
Page | 21 of 23
Appendix Table 2: Aneuploidy Detection by Sequencing in
Average
Singleton Pregnancies: Test Performance
Studya N, Final
Analysisb
Indeterminate
Samples
(low fetal DNA
or test failure)
Sensitivity, % (95% CI) Specificity, % (95% CI)
T21 T13 T18 T21 T13 T18
Illumina (Verifi)
Zhang et
al (2015)22
Zhang et al
(2015)22
Zhan
g et al
(2015)
22
Bianchi
(2014)14
Total
N=1914
T21: n=5
T18: n=2
T13: n=1
39/2042 (2%)
100 (47.8 to
100)
100
(15.8
to
100)
99.7
(99.3
to
99.9)
99.8
(99.6 to 100)
Ariosa (Harmony)
Nicolaides
(2012)40
Total
N=2049
T21: n=8
T18: n=3
100/2029 (4.9%)
100 100
Norton
(2015)21
Total
N=15,841
T21: n=38
T18: n=10
T13: n=6
488/16,329 (3%) 100
(90.7 to 100)
100
(15.8 to
100)
90.0
(55.5
to
99.7)
99.9
(99.9
to
100)
100
(99.9
to 100)
100
(99.9 to 100)
Natera (Panorama)
Pergament
et al
(2014)41
Total N=1051 85/1051 (8) 100
(93.8 to 99.8)
100
(73.5 to
100)
96
(79.7
to
99.9)
100
(99.6
to 100)
100
(99.6 to
100)
99.9
(99.4 to 100)
CI: confidence interval; T13: trisomy 13; T18: trisomy 18; T21:
trisomy 21. a All studies had industry-funding.
-
Page | 22 of 23
History
Date Comments 03/11/13 New Policy. Add to Ob/Gyn/Reproduction
section, considered medically necessary for
high-risk singleton pregnancies.
07/12/13 Coding update. MAAA code 0005M added to the policy.
09/09/13 Interim update. Regulatory status on Nateras Panorama
updated. CPT code 81507 for
Harmony added. Brand names of 4 tests added as examples to
policy statement.
08/11/14 Annual Review. Policy updated with literature review
through April 8, 2014. References
13 and 14 added. Title changed to: Noninvasive Prenatal Testing
for Trisomy 21 Using
Cell Free Fetal DNA. Policy statement on average risk
pregnancies changed from not
medically necessary to investigational. Coding update: notation
made that 0005M was
deleted as of 12/31/13 and replaced with 81507; CPT codes
re-arranged to be in
numerical order; ICD-9 and ICD-10 diagnosis codes removed.
12/22/14 Update Related Policies. Add 12.04.116
1/14/15 Coding update. CPT code 81420, effective 1/1/15, added
to policy; deleted code
modifier 0005M removed.
02/10/15 Annual Review. Policy updated with literature review
through October 1, 2014.
Statement added that concurrent nucleic acid sequencing-based
testing of maternal
plasma for trisomy 13 and/or 18 may be considered medically
necessary in women
who are eligible for and are undergoing nucleic acid
sequencing-based testing of
maternal plasma for trisomy 21. In addition, 2 investigational
statements were added,
1 for nucleic acid sequencing-based testing of maternal plasma
for trisomy 13 and/or
18, other than in the situations specified in the medically
necessary statement and the
other for fetal sex chromosome aneuploidies. References 4, 16,
20, and 24 added. In
title, Trisomy 21 changed to Fetal Aneuploidies.
06/19/15 Coding update. CPT code 0009M, effective 7/1/15, added
to policy.
08/11/15 Annual Review. Policy updated with literature review on
average-risk women through
June 29, 2015. High-risk removed from medically necessary
statement.
Investigational statement on average-risk women removed. In
title, testing changed
to screening. References 20 and 24 added. CPT code 88271 added
to policy Coding
section.
12/08/15 Annual Review. Policy updated with literature review
through August 31, 2015;
references 1, 4, 20-21, 25-28, 31, and 34-35 added. Statement
added that nucleic acid
sequencing-based testing of maternal plasma for microdeletions
is considered
investigational. Added and Microdeletions to title.
12/01/16 Annual Review, approved November 8, 2016. Policy
updated with literature review
through August 25, 2016. References 8-9, 27, 34-35, and 38
added. No change to
-
Page | 23 of 23
Date Comments policy statement.
01/01/17 Coding update; added new CPT code 81422 effective
1/1/17.
10/01/17 Annual Review, approved September 21, 2017. Policy
updated with literature review
through June 22, 2017; references 10, 25-27, and 40-41 added;
note 35 replaced.
Removed CPT code 88271. Policy statements unchanged.
03/09/18 Minor update; added Documentation Requirements
section.
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CPT codes, descriptions and materials are copyrighted by the
American Medical Association (AMA). 2018 Premera
All Rights Reserved.
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benefit booklet or contact a customer service representative to
determine whether there are any benefit limitations
applicable to this service or supply. This medical policy does
not apply to Medicare Advantage.
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037338 (07-2016)
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(TTY: 800-842-5357)
:(Arabic) .
Premera Blue Cross. . . . (TTY: 800-842-5357) 1471-722-800
(Chinese): Premera Blue Cross
800-722-1471 (TTY: 800-842-5357)
Oromoo (Cushite): Beeksisni kun odeeffannoo barbaachisaa qaba.
Beeksisti kun sagantaa yookan karaa Premera Blue Cross tiin
tajaajila keessan ilaalchisee odeeffannoo barbaachisaa qabaachuu
dandaa. Guyyaawwan murteessaa taan beeksisa kana keessatti ilaalaa.
Tarii kaffaltiidhaan deeggaramuuf yookan tajaajila fayyaa
keessaniif guyyaa dhumaa irratti wanti raawwattan jiraachuu dandaa.
Kaffaltii irraa bilisa haala taeen afaan keessaniin odeeffannoo
argachuu fi deeggarsa argachuuf mirga ni qabaattu. Lakkoofsa
bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa. Franais
(French): Cet avis a d'importantes informations. Cet avis peut
avoir d'importantes informations sur votre demande ou la couverture
par l'intermdiaire de Premera Blue Cross. Le prsent avis peut
contenir des dates cls. Vous devrez peut-tre prendre des mesures
par certains dlais pour maintenir votre couverture de sant ou
d'aide avec les cots. Vous avez le droit d'obtenir cette
information et de laide dans votre langue aucun cot. Appelez le
800-722-1471 (TTY: 800-842-5357). Kreyl ayisyen (Creole): Avi sila
a gen Enfmasyon Enptan ladann. Avi sila a kapab genyen enfmasyon
enptan konsnan aplikasyon w lan oswa konsnan kouvti asirans lan
atrav Premera Blue Cross. Kapab genyen dat ki enptan nan avi sila
a. Ou ka gen pou pran kk aksyon avan sten dat limit pou ka kenbe
kouvti asirans sante w la oswa pou yo ka ede w avk depans yo. Se
dwa w pou resevwa enfmasyon sa a ak asistans nan lang ou pale a,
san ou pa gen pou peye pou sa. Rele nan 800-722-1471 (TTY:
800-842-5357). Deutsche (German): Diese Benachrichtigung enthlt
wichtige Informationen. Diese Benachrichtigung enthlt unter
Umstnden wichtige Informationen bezglich Ihres Antrags auf
Krankenversicherungsschutz durch Premera Blue Cross. Suchen Sie
nach eventuellen wichtigen Terminen in dieser Benachrichtigung. Sie
knnten bis zu bestimmten Stichtagen handeln mssen, um Ihren
Krankenversicherungsschutz oder Hilfe mit den Kosten zu behalten.
Sie haben das Recht, kostenlose Hilfe und Informationen in Ihrer
Sprache zu erhalten. Rufen Sie an unter 800-722-1471 (TTY:
800-842-5357). Hmoob (Hmong): Tsab ntawv tshaj xo no muaj cov
ntshiab lus tseem ceeb. Tej zaum tsab ntawv tshaj xo no muaj cov
ntsiab lus tseem ceeb txog koj daim ntawv thov kev pab los yog koj
qhov kev pab cuam los ntawm Premera Blue Cross. Tej zaum muaj cov
hnub tseem ceeb uas sau rau hauv daim ntawv no. Tej zaum koj kuj
yuav tau ua qee yam uas peb kom koj ua tsis pub dhau cov caij nyoog
uas teev tseg rau hauv daim ntawv no mas koj thiaj yuav tau txais
kev pab cuam kho mob los yog kev pab them tej nqi kho mob ntawd.
Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau ua
koj hom lus pub dawb rau koj. Hu rau 800-722-1471 (TTY:
800-842-5357). Iloko (Ilocano): Daytoy a Pakdaar ket naglaon iti
Napateg nga Impormasion. Daytoy a pakdaar mabalin nga adda ket
naglaon iti napateg nga impormasion maipanggep iti apliksayonyo
wenno coverage babaen iti Premera Blue Cross. Daytoy ket mabalin
dagiti importante a petsa iti daytoy a pakdaar. Mabalin nga adda
rumbeng nga aramidenyo nga addang sakbay dagiti partikular a
naituding nga aldaw tapno mapagtalinaedyo ti coverage ti salun-atyo
wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti daytoy
nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti
bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357).
Italiano (Italian): Questo avviso contiene informazioni importanti.
Questo avviso pu contenere informazioni importanti sulla tua
domanda o copertura attraverso Premera Blue Cross. Potrebbero
esserci date chiave in questo avviso. Potrebbe essere necessario un
tuo intervento entro una scadenza determinata per consentirti di
mantenere la tua copertura o sovvenzione. Hai il diritto di
ottenere queste informazioni e assistenza nella tua lingua
gratuitamente. Chiama 800-722-1471 (TTY: 800-842-5357).
-
(Japanese): Premera Blue Cross
800-722-1471 (TTY: 800-842-5357) (Korean): . Premera Blue Cross
. . . . 800-722-1471 (TTY: 800-842-5357) . (Lao): . Premera Blue
Cross. . . . 800-722-1471 (TTY: 800-842-5357). (Khmer):
Premera Blue Cross
800-722-1471 (TTY: 800-842-5357) (Punjabi): . Premera Blue Cross
. . , , 800-722-1471 (TTY: 800-842-5357).
:(Farsi) .
. Premera Blue Cross .
. .
)800-842-5357 TTY( 800-722-1471 .
Polskie (Polish): To ogoszenie moe zawiera wane informacje. To
ogoszenie moe zawiera wane informacje odnonie Pastwa wniosku lub
zakresu wiadcze poprzez Premera Blue Cross. Prosimy zwrcic uwag na
kluczowe daty, ktre mog by zawarte w tym ogoszeniu aby nie
przekroczy terminw w przypadku utrzymania polisy ubezpieczeniowej
lub pomocy zwizanej z kosztami. Macie Pastwo prawo do bezpatnej
informacji we wasnym jzyku. Zadzwocie pod 800-722-1471 (TTY:
800-842-5357). Portugus (Portuguese): Este aviso contm informaes
importantes. Este aviso poder conter informaes importantes a
respeito de sua aplicao ou cobertura por meio do Premera Blue
Cross. Podero existir datas importantes neste aviso. Talvez seja
necessrio que voc tome providncias dentro de determinados prazos
para manter sua cobertura de sade ou ajuda de custos. Voc tem o
direito de obter esta informao e ajuda em seu idioma e sem custos.
Ligue para 800-722-1471 (TTY: 800-842-5357).
Romn (Romanian): Prezenta notificare conine informaii
importante. Aceast notificare poate conine informaii importante
privind cererea sau acoperirea asigurrii dumneavoastre de sntate
prin Premera Blue Cross. Pot exista date cheie n aceast notificare.
Este posibil s fie nevoie s acionai pn la anumite termene limit
pentru a v menine acoperirea asigurrii de sntate sau asistena
privitoare la costuri. Avei dreptul de a obine gratuit aceste
informaii i ajutor n limba dumneavoastr. Sunai la 800-722-1471
(TTY: 800-842-5357). P (Russian): . Premera Blue Cross. . , , . .
800-722-1471 (TTY: 800-842-5357). Faasamoa (Samoan): Atonu ua iai i
lenei faasilasilaga ni faamatalaga e sili ona taua e tatau ona e
malamalama i ai. O lenei faasilasilaga o se fesoasoani e faamatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e
tau fia maua atu i ai. Faamolemole, ia e iloilo faalelei i aso
faapitoa oloo iai i lenei faasilasilaga taua. Masalo o lea iai ni
feau e tatau ona e faia ao lei aulia le aso ua taua i lenei
faasilasilaga ina ia e iai pea ma maua fesoasoani mai ai i le
polokalame a le Malo oloo e iai i ai. Oloo iai iate oe le aia tatau
e maua atu i lenei faasilasilaga ma lenei famatalaga i legagana e
te malamalama i ai aunoa ma se togiga tupe. Vili atu i le telefoni
800-722-1471 (TTY: 800-842-5357). Espaol (Spanish): Este Aviso
contiene informacin importante. Es posible que este aviso contenga
informacin importante acerca de su solicitud o cobertura a travs de
Premera Blue Cross. Es posible que haya fechas clave en este aviso.
Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura mdica o ayuda con los costos.
Usted tiene derecho a recibir esta informacin y ayuda en su idioma
sin costo alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog): Ang Paunawa na ito ay naglalaman ng mahalagang
impormasyon. Ang paunawa na ito ay maaaring naglalaman ng
mahalagang impormasyon tungkol sa iyong aplikasyon o pagsakop sa
pamamagitan ng Premera Blue Cross. Maaaring may mga mahalagang
petsa dito sa paunawa. Maaring mangailangan ka na magsagawa ng
hakbang sa ilang mga itinakdang panahon upang mapanatili ang iyong
pagsakop sa kalusugan o tulong na walang gastos. May karapatan ka
na makakuha ng ganitong impormasyon at tulong sa iyong wika ng
walang gastos. Tumawag sa 800-722-1471 (TTY: 800-842-5357). (Thai):
Premera Blue Cross 800-722-1471 (TTY: 800-842-5357) (Ukrainian): .
Premera Blue Cross. , . , , . . 800-722-1471 (TTY: 800-842-5357).
Ting Vit (Vietnamese): Thng bo ny cung cp thng tin quan trng. Thng
bo ny c thng tin quan trng v n xin tham gia hoc hp ng bo him ca qu
v qua chng trnh Premera Blue Cross. Xin xem ngy quan trng trong
thng bo ny. Qu v c th phi thc hin theo thng bo ng trong thi hn duy
tr bo him sc khe hoc c tr gip thm v chi ph. Qu v c quyn c bit thng
tin ny v c tr gip bng ngn ng ca mnh min ph. Xin gi s 800-722-1471
(TTY: 800-842-5357).