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.

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

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-

trimester population. Am J Obstet Gynecol. Nov 2012;207(5):374 e371-376. PMID 23107079

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.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The

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local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review

and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit

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All Rights Reserved.

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determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to

the limits and conditions of the member benefit plan. Members and their providers should consult the member

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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(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).