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
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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
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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.
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10. Iwarsson E, Jacobsson B, Dagerhamn J, et al. Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18
and 13 in a general pregnant population and in a high risk 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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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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applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
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(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
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Premera Blue Cross
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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).
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