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Noninvasive Prenatal Screening for Fetal Aneuploidies and Microdeletions Using Cell Free Fetal DNA

Policy Number: MP-519

Latest Review Date: November 2020

Category: Laboratory

Policy Grade: A

POLICY:

Effective for dates of service January 1, 2021 and after:

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 may be considered medically necessary in women with high-risk singleton or high-risk twin pregnancies undergoing screening for trisomy 21 and are at a minimum of 10 weeks gestation and who meet at least ONE of the following criteria:

  • Maternal age 35 years or older at delivery; OR
  • Fetal ultrasonographic findings indicating increased risk of aneuploidy; OR
  • History of previous pregnancy with a trisomy; OR
  • Standard serum screening test positive for aneuploidy; OR
  • Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21

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.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered investigational for women with average-risk singleton or average-risk twin pregnancy.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered and investigational in women with high-order multiple gestation (i.e. triplets or higher) pregnancies.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above, is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for fetal sex chromosome aneuploidies is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for microdeletions is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for twin zygosity is considered investigational.

Vanadis NIPT of maternal plasma to screen for trisomy 21, 18 and 13 is considered  investigational in all situations.

Effective for dates of service prior to January 1, 2021:

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 may be considered medically necessary in women with high-risk singleton pregnancies undergoing screening for trisomy 21 and are at a minimum of 10 weeks gestation and who meet at least ONE of the following criteria:

  • Maternal age 35 years or older at delivery; OR
  • Fetal ultrasonographic findings indicating increased risk of aneuploidy; OR
  • History of previous pregnancy with a trisomy; OR
  • Standard serum screening test positive for aneuploidy; OR
  • Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21

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.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered investigational for women with average-risk singleton pregnancy.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered  investigational in women with twin or multiple pregnancies.

Nucleic acid sequencing-based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above, is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for fetal sex chromosome aneuploidies is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for microdeletions is considered investigational.

Nucleic acid sequencing-based testing of maternal plasma for twin zygosity is considered investigational.

Vanadis NIPT of maternal plasma to screen for trisomy 21, 18 and 13 is considered investigational in all situations.

DESCRIPTION OF PROCEDURE OR SERVICE:

National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, most of which are aneuploidies, an abnormal number of chromosomes. Trisomy syndromes are aneuploidies involving three copies of one chromosome. Trisomies 21 (T21), 18 (T18), and 13 (T13) are the most common forms of fetal aneuploidy. Fetuses with T18 and T13 generally do not survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Noninvasive prenatal screening (NIPS) analyzing cell-free fetal DNA in maternal serum is a potential complement or alternative to conventional serum screening. NIPS using cell-free fetal DNA has also been proposed to screen for microdeletions.

Fetal Aneuploidy

Fetal chromosomal abnormalities occur in approximately one in 160 live births. The majority of fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving three 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 one in 1100 at age 25 to 29. The risk of a fetus with T21 (at 16 weeks of gestation) is about one in 250 at age 35 and one in 75 at age 40.

Trisomy 21 (T21, Down syndrome) is the most common chromosomal aneuploidy 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. Detection of T18 and T13 early in pregnancy can facilitate preparation for fetal loss or early intervention.

Fetal Aneuploidy Screening

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 procedure-associated risks of fetal injury, fetal loss, and infection. A new screening strategy that reduces unnecessary amniocentesis and CVS procedures or 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 has recently become available and has the potential to substantially alter the current approach to screening. The test technology involves the detection of fetal cell-free DNA fragments present in the plasma of pregnant women. As early as eight to ten 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 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.

Twin Zygosity Testing

Twin gestations occur in approximately one in 30 live births in the United States and have a four- to ten-fold increased risk of perinatal complications. Dizygotic or "fraternal" twins occur from ovulation and fertilization of two oocytes, which results in dichorionic (DC) placentation and two separate placentas. In contrast to DC twins, MC twin pregnancies share their blood supply. Monochorionic (MC) twins account for about 20% of twin gestations and are at higher risk of structural defects, miscarriage, preterm delivery, and selective fetal growth restriction compared to DC twins. Up to 15% of MC twin pregnancies are affected by twin to twin transfusion syndrome (TTTS), a condition characterized by relative hypovolemia of one twin and hypervolemia of the other. According to estimates from live births, TTTS occurs in up to 15% of MC twin pregnancies. In these twin pregnancies, serial fetal ultrasound examinations are necessary to monitor for development of TTTS as well as selective intrauterine growth restriction because these disorders have high morbidity and mortality, and are amenable to interventions that can improve outcomes. Noninvasive prenatal testing (NIPT) using cell-free fetal DNA to determine zygosity in twin pregnancies could potentially inform decisions about early surveillance for TTTS and other MC twin-related abnormalities. In particular, determining zygosity with NIPT could potentially assist in the assessment of chorionicity when ultrasound findings are not clear.

Cell-Free Fetal DNA Analysis Methods

Sequencing-based tests use one of two 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 shotgun 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 in order 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.

The second general approach is single nucleotide variant-based methods. They use targeted amplification and analysis of approximately 20,000 single nucleotide variants on selected chromosomes (e.g., 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.

A newer approach to cell free DNA testing called the Vanadis NIPT does not involve amplification or sequencing. The assay uses maternal serum and applies a series of enzymes to create labelled rolling circle replication products (RCPs) from chromosomal cell-free DNA targets, which are then converted to fluorescent DNA molecules and labeled with chromosome-specific fluorophores. The labeled fluorescent DNA molecules are deposited to a microfilter plate and counted with an automated imaging device. The ratio between the number of each chromosome-specific fluorescent DNA molecules is transferred for risk calculation to proprietary software to calculate the likelihood of a trisomy. Currently, Vanadis NIPT provides results for trisomy 21, trisomy 18 and trisomy 13; although, additional aneuploidies and microdeletions might be added in the future.

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 one and three 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.

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-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 one in 4000 to one in 6395 live births. Prevalence estimates for other microdeletions are between one in 5000 and one in 10,000 live births for 1p36 deletion syndrome, between one in 10,000 and one in 30,000 for Prader-Willi syndrome, and between one in 12,000 and one 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.

Table 1. Recurrent Microdeletion Syndromes

Syndrome

Location

Estimated Prevalence

DiGeorge

22q11.2

1/2000

1p36 deletion

1p36-

1/5000

Prader-Willi and Angelman

Del 15q11.2

1/20,000

Wolf-Hirschhorn

4p-

1/50,000 to 1/20,000

Cri du chat

5p-

1/50,000

Miller-Dieker

Del 17p13.3

1 /100,000

Adapted from Chitty et al (2018).

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 (e.g., 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 (e.g., 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 (e.g., 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.

KEY POINTS:

The policy is based on literature reviews, most recently through October 2020. Moreover, the policy is informed by two TEC Assessments. A 2013 TEC Assessment focused on detection of trisomy 21 (T21) and a 2014 TEC Assessment addressed detection of fetal aneuploidies other than T21 (specifically trisomies 13 and 18, and fetal sex chromosome aneuploidies).

Summary of Evidence

For individuals who have a twin or singleton pregnancy who receive NIPS for T21, T18, and T13 using cell-free fetal DNA, the evidence includes observational studies and systematic reviews. The relevant outcomes are test accuracy and validity, morbid events, and resource utilization. Published studies on 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. 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 for T21 will result in fewer missed cases of Down syndrome, fewer invasive procedures, and fewer cases of pregnancy loss following invasive procedures. Screening for T18 and T13 along with T21 may allow for preparation for fetal demise or termination of the pregnancy prior to fetal loss. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome for women who are high risk.

For individuals who have a twin or singleton average risk pregnancy who receive NIPS for sex chromosome aneuploidies using cell-free fetal DNA, the evidence includes observational studies, mainly in high-risk pregnancies, and systematic reviews. The 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 makes definitive conclusions difficult. In addition, the clinical utility of identifying sex chromosome aneuploidies during pregnancy is uncertain. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a twin or multiple average risk pregnancy who receive NIPS for aneuploidies using cell-free fetal DNA, the evidence includes several observational studies and systematic reviews. The 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 the paucity of evidence on clinical validity. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with average risk pregnancy (ies) who receive NIPS for microdeletions using cell-free fetal DNA, the evidence includes several observational studies. The relevant outcomes are test accuracy and validity, morbid events, and resource utilization. The available studies on clinical validity have limitations (e.g., 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.

For individuals who have average risk twin pregnancy who receive noninvasive prenatal testing (NIPT) for twin zygosity using cell-free fetal DNA, the evidence includes an observational study. Relevant outcomes are test accuracy and validity, morbid events, and resource utilization. Sensitivity and specificity were high (100%) in one validation study conducted in 95 twin gestations. This evidence is too limited to draw conclusions about performance characteristics and would need to be confirmed in additional, well-conducted studies. Moreover, the clinical utility of NIPT for twin zygosity compared to standard methods such as ultrasound is unclear and has not been evaluated in published studies. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have an average risk twin or singleton pregnancy who receive NIPS for T21, T18, and T13 using Vanadis NIPT, the evidence includes two industry sponsored studies. Relevant outcomes are test accuracy and validity, morbid events, and resource utilization. The available studies on clinical validity have limitations, and the added benefit of Vanadis NIPT compared with current approaches is unclear. Moreover, the clinical utility of Vanadis NIPT remains unclear and has not been evaluated in published studies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, 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 through three physician specialty societies and four academic medical centers while this policy was under review in 2012. There was consensus that sequencing-based tests to determine T21 from maternal plasma 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 society’s input, does not recommend the new tests at this time for women with singleton pregnancies who are not at high risk of aneuploidy. There was consensus that sequencing-based tests to determine T21 from maternal plasma DNA are investigational for women with multiple pregnancies. In terms of an appropriate protocol for using sequencing-based testing, there was consensus that testing should not be used as a single-screening test without confirmation of results by karyotyping. There was mixed input on use of the test as a replacement for standard screening tests with karyotyping confirmation and use as a secondary screen in women with screen positive on standard screening tests with karyotyping confirmation. Among the five reviewers who responded to the following questions (which did not include ACOG), there was consensus that the modeling approach is sufficient to determine the clinical utility of the new tests and near-consensus there is a not a 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 (ACOG) and Society for Maternal-Fetal Medicine (2016) released a joint practice bulletin summary (No. 163) on screening for fetal aneuploidy. 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.”
  • “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 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.”

American College of Medical Genetics and Genomics (ACMG)

In 2016, the American College of Medical Genetics and Genomics (ACMG) published a position statement on noninvasive prenatal screening (NIPS) for fetal aneuploidy. The relevant recommendations are as follows.

  • “Informing all pregnant women that NIPS is the most sensitive screening option for traditionally screened aneuploidies (i.e., 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.”

The American College of Medical Genetic and Genomics did not recommend “NIPS to screen for autosomal aneuploidies other than those involving chromosomes 13, 18, and 21.”

International Society for Prenatal Diagnosis (ISPD)

In 2015, the International Society for Prenatal Diagnosis published a position statement on prenatal diagnosis of chromosomal abnormalities, an update of their 2013 statement. (Note that a number of the authors of the 2015 report had financial links to industry.) Following is the summary of recommendations:

  • “High sensitivities and specificities are potentially achievable with cfDNA [cell-free DNA] screening for some fetal aneuploidies, notably trisomy 21.
  • Definitive diagnosis of Down syndrome and other fetal chromosome abnormalities can only be achieved through testing on cells obtained by amniocentesis or CVS.
  • The use of maternal age alone to assess fetal Down syndrome risk in pregnant women is not recommended.
  • 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.
  • A four-marker serum test should be available to women who first attend for their prenatal care after 13 weeks six days of pregnancy and where cfDNA screening cannot be provided.
  • Protocols that combine first trimester and second trimester conventional markers are valid.
  • Second trimester ultrasound can be a useful adjunct to conventional aneuploidy screening protocols.
  • 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 had been addressed in the 1990s, but the topic is no longer listed on the Task Force website.

KEY WORDS:

Down syndrome, Maternal Plasma DNA Testing, Fetal DNA, Maternal Plasma Testing, Prenatal Detection, Trisomy 21, Trisomy 21 Testing, Trisomy 18, Trisomy 13, Screening, Massively parallel-sequencing, MaterniT21, Sequenom, Ariosa, Verinata, Verifi, 0005M, Panorama, Harmony, Illumina, Natera, InformaSeq, QNatal, Microdeletion, Microdeletions, VisibiliT™, Twin zygosity, Panorama, NIPS, Noninvasive Prenatal Testing, Noninvasive Prenatal Screening, Edwards syndrome, Patau syndrome, Vanadis, PerkinElmer, Varacity, NIPD Genetics

APPROVED BY GOVERNING BODIES:

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 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:

  • Myriad Prequel(TM) Prenatal Screen (Myriad Women's Health, Counsyl) utilizes whole genome sequencing for detecting aneuploidy including T21, T18, T13
  • The VisibiliT™ (Sequenom Laboratories, now LabCorp) tests for T21 and T18, and tests for sex.  
  • MaterniT21™ PLUS (Sequenom Laboratories, now LabCorp) core test includes T21, T18, T13, and fetal sex aneuploidies. The enhanced sequencing series includes testing for T16, 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 1 of 3 categories: no aneuploidy detected, aneuploidy detected, or aneuploidy suspected.
  • InformaSeqSM (Integrated Genetics, now LabCorp) is a prenatal test for detecting T21, T18, and T13, with optional testing for select sex chromosome abnormalities. It uses the Illumina platform and reports results in a similar manner.
  • QNatal Advanced™ (Quest Diagnostics) tests for T21, T18, and T13.
  • Vanadis NIPT Solution (PerkinElmer) tests for T21, T18, and T13.
  • Veracity (NIPD Genetics) tests for T21, T18, and T13, sex chromosome aneuploidies, and microdeletions.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

0060U  

Twin zygosity, genomic targeted sequence analysis of chromosome 2, using circulating cell-free fetal DNA in maternal blood. (Effective 07/01/2018)

(Includes Twins Zygosity PLA, Natera, Inc.)

81420

Fetal Chromosomal aneuploidy (e.g., 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 (i.e., DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA in maternal blood

(Specific code for testing maternal blood for fetal chromosomal microdeletion(s))

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

(Specific MAAA CPT code for the Ariosa Diagnostics Harmony™ Prenatal Test)

88271

Molecular cytogenetics; DNA probe, each (e.g., FISH)

If none of the above codes are appropriate, the below unlisted codes might be used:

81479

Unlisted molecular pathology procedure

81599

Unlisted multianalyte assay with algorithmic analysis

84999

Unlisted chemistry procedure

PREVIOUS CODING:

CPT codes:

0168U

Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma without fetal fraction cutoff, algorithm reported as a risk score for each trisomy (Deleted 10/1/2021)

(Includes Vanadis NIPT, PerkinElmer, Inc.) 

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 (Deleted 12/31/2019)

(multianalyte assays with algorithmic analyses (MAAA) administrative code specific to the VisibiliT™ test)

REFERENCES:

  1. Allyse, MM, Wick, MM. Noninvasive Prenatal Genetic Screening Using Cell-free DNA. JAMA, 2018 Aug 4; 320(6).
  2. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion: Screening for fetal chromosomal abnormalities. No. 226. Obstet Gynecol. 2020; 136 (4): 859-867.
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  14. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Noninvasive maternal plasma sequencing-based screening for fetal aneuploidies other than trisomy 21. TEC Assessments 2014; Volume 29, Tab 7.
  15. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Sequencing-based tests to determine fetal Down syndrome (trisomy 21) from maternal plasma DNA. TEC Assessments 2013; Volume 27, Tab 10.
  16. Boelig R, Saccone G, Bellussi F, Berghella V. MFM guidance for COVID-19. Am J Obstet Gynecol MFM 2020.
  17. Canick JA, Kloza EM, Lambert-Messerlian GM et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. May 14 2012:1-5.
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  19. Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. Obstet Gynecol. Jun 25 2015.
  20. 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):291-5.
  21. Dondorp W, de Wert G, Bombard Y, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations. Eur J Hum Genet. Apr 1 2015.
  22. 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.
  23. 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.
  24. Fairbrother G, Burigo J, Sharon T, Song K. Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis. J Matern Fetal Neonatal Med, Early Online: 1–5. 2015 Ariosa Diagnostics. DOI: 10.3109/14767058.2015.1038703. http://informahealthcare.com/jmf. ISSN: 1476-7058 (print), 1476-4954 (electronic).
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  26. 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.
  27. Galeva, SS, Konstantinidou, LL, Gil, MM, Akolekar, RR, Nicolaides, KK. Routine first-trimester screening for fetal trisomies in twin pregnancy: cell-free DNA test contingent on results from combined test. Ultrasound Obstet Gynecol, 2018 Oct 26; 53(2).
  28. Garfield SS, Armstrong SO. Clinical and cost consequences of incorporating a novel non-invasive prenatal test into the diagnostic pathway for fetal trisomies. Journal of Managed Care Medicine 2012; 15(2):34-41.
  29. 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. 2017 Sep; 50(3):302-314. Update in: Ultrasound Obstet Gynecol. 2019 Jun; 53(6):734-742.
  30. 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.
  31. Gil, MM, Galeva, SS, Jani, JJ, Konstantinidou, LL, Akolekar, RR, Plana, MM, Nicolaides, KK. Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta-analysis. Ultrasound Obstet Gynecol, 2019 Jun; 53(6).
  32. Gil MM, Quezada MS, Bregant B et al. Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. Ultrasound Obstet Gynecol 2013; 42(1):34-40.
  33. Gregg AR, Gross SJ, Best RG et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med 2013; 15(5):395-398.
  34. 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.
  35. Gross SJ, Stosic M, McDonald-McGinn DM, et al. Clinical Experience with Single-Nucleotide Polymorphism-Based Noninvasive Prenatal Screening for 22q11.2 Deletion Syndrome. Ultrasound Obstet Gynecol. Feb 2016; 47(2):177-183.
  36. 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.
  37. Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. Apr 15 1983; 249(15):2034-2038.
  38. Hu, HH, Wang, LL, Wu, JJ. Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 8141 single pregnancies. Hum. Genomics, 2019 Mar 16; 13(1).
  39. 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.
  40. Le Conte, GG, Letourneau, AA, Jani, JJ. Cell-free fetal DNA analysis in maternal plasma as screening test for trisomies 21, 18 and 13 in twin pregnancy. Ultrasound Obstet Gynecol, 2017 Aug 24; 52(3).
  41. Liao H, Liu S, Wang H. Performance of non-invasive prenatal screening for fetal aneuploidy in twin pregnancies: a meta-analysis. Prenat Diagn. Sep 2017; 37(9):874-882.
  42. 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. May 31 2016.
  43. National Society of Genetic Counselors (NSGC). Noninvasive prenatal testing/ noninvasive prenatal diagnosis (NIPT/NIPD) Available online at: www.nsgc.org/Advocacy/PositionStatements/tabid/107/Default.aspx. Last accessed October, 2012.
  44. 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 2012; 207(5):374.e1-6.
  45. 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 2013; 33(6):575-579.
  46. 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.
  47. 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 2012; 207(2):1e131-138.
  48. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. Apr 23 2015; 372(17):1589-1597.
  49. Ohno M, Caughey A. The role of noninvasive prenatal testing as a diagnostic versus a screening tool--a cost-effectiveness analysis. Prenat Diagn 2013; 33(7):630-635.
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  52. 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 2012; 14(3):296-305.
  53. 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 2011; 13(11):913-920.
  54. 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.
  55. Petersen AK, Cheung SW, Smith JL, et al. Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory. Am J Obstet Gynecol. Dec 2017; 217(6):691 e691-691 e696.
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POLICY HISTORY:

Medical Policy Panel January 2013

Medical Policy Group, January 2013 (1): New policy adopted for nucleic sequencing-based testing of maternal plasma for trisomy 21; coverage criteria has been in effect since November 2012 prior to creation of policy

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Group, March 2013 (1): Added unlisted codes 81479 and 84999 to the coding section due to each manufacturer wanting to use different unlisted codes for billing.

Medical Policy Group, July 2013 (1): Added CPT code 0005M to coding section, effective for usage on 07/01/2013

Medical Policy Group, December 2013 (1): 2014 Coding Update: added new code 81507, effective 01/01/14; moved deleted code 0005M to previous coding, effective 12/31/2013

Medical Policy Panel, May 2014

Medical Policy Group, June 2014 (1): Title changed to Noninvasive Prenatal Testing for Trisomy 21 Using Cell Free Fetal DNA; update to Key Points and References; no change to policy statement

Medical Policy Administration Committee, July 2014

Medical Policy Group, November 2014(4): 2015 Annual Coding update. Added code 81420 to current coding.

Medical Policy Panel, November 2014

Medical Policy Group, February 2015 (3): Updates to Title, Description, Policy, Key Points and References; Policy statement expanded to include T13 and T18.

Available for comment February 21 through April 6, 2015

Medical Policy Group, July 2015 (4): 2015 Quarterly Coding Update. Added CPT code 0009M to current coding section.

Medical Policy Panel, July 2015

Medical Policy Group, August 2015 (3): 2015 Updates to Title, Description, Key Points, References & Appendix; no change in policy statement

Medical Policy Panel, October 2015

Medical Policy Group, January 2016 (3): Description, Key Points, Key Words, Governing Bodies & Coding sections updated with literature review through August 31, 2015; References updated; Policy statement updated to clarify that nucleic acid sequencing-based testing of maternal plasma for microdeletions does not meet medical criteria for coverage and is considered investigational; “And Microdeletions” added to Title

Medical Policy Panel, October 2016

Medical Policy Group, October 2016 (3): 2016 Updates to Key Points & References; no change in policy statement.

Medical Policy Panel, September 2017

Medical Policy Group, September 2017 (3): 2017 Updates to Description, Key Points, Key Words, Governing Bodies, Coding & Reference sections; no change in policy statement; removed previous coding section containing code 0005M deleted 12/31/13

Medical Policy Group, June 2018: Quarterly Coding Update, July 2018. Added new CPT code 0060U to Current Coding. Added Key Words twin zygosity, Panorama.

Medical Policy Panel, August 2018

Medical Policy Group, February 2019 (9): Annual updates to Description, Key Points, References. No change to policy statement. Added key words: NIPS, Noninvasive Prenatal Testing, Noninvasive Prenatal Screening, Edwards syndrome, Patau syndrome

Medical Policy Panel, August 2019

Medical Policy Group, August 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Created Previous Coding section to include code 0009M. Updated Key Points.

Medical Policy Panel, August 2020

Medical Policy Group, August 2020 (9): 2020 Updates to Description, Key Points, References. Added investigational statements regarding nucleic acid sequencing-based testing of maternal plasma for twin zygosity and Vanadis NIPT (This is not a stance change). Key words added: Vanadis, PerkinElmer, Varacity, NIPD Genetics. Added CPT code 0168U (Vanadis NIPT) to current coding section.

Medical Policy Group, November 2020 (9): Updates to Policy Statement, Key Points, and References. Prenatal cell-free DNA (cfDNA) screening was expanded to cover screening in high risk twin pregnancies, effective 1/1/2021.

Medical Policy Administration Committee, December 2020.

Medical Policy Group, September 2021: Quarterly Coding Update, October 2021. Moved CPT code 0168U from current coding section to previous coding section. Policy statement updated to remove “not medically necessary,” no change to policy intent.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.