Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, Single-Gene Disorders, and Twin Zygosity Using Cell-Free Fetal DNA

POLICY NUMBER

A.4.01.21

DESCRIPTION

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 3 copies of one chromosome. Trisomies 21, 18, and 13 are the most common forms of fetal aneuploidy that survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Noninvasive prenatal screening analyzing fetal cell-free DNA (cfDNA) in maternal serum is a potential complement or alternative to conventional serum screening. Noninvasive prenatal screening using cell-free fetal DNA has also been proposed to screen for microdeletions. Prenatal testing for twin zygosity using cell-free fetal DNA has been proposed to inform decisions about early surveillance for twin-twin transfusion syndrome and other monochorionic twin-related abnormalities.

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 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 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.

Trisomy 21 is the most common chromosomal aneuploidy. 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 ScreeningStandard aneuploidy screening involves combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy. The detection rate for various combinations of non-invasive 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 is required to confirm that T21 or another trisomy is present. Both amniocentesis and chorionic villous sampling are invasive procedures and have procedure-associated risks of fetal injury, fetal loss, and infection. A new screening strategy that reduces unnecessary amniocentesis and chorionic villous sampling procedures or increases detection of T21, T18, and T13 could improve outcomes. Confirmation of positive non-invasive screening tests with amniocentesis or chronic villous sampling is recommended. Amniocentesis might be preferred over chorionic villus sampling for confirming cell-free DNA positive results due to the potential for placental mosaicism leading to false positive results. With more accurate screening tests, fewer individuals would receive positive screening results.

Commercial, noninvasive, sequencing-based testing of maternal serum for fetal trisomy syndromes is now available. The testing technology involves the 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 fetal cell-free DNA in a maternal plasma sample. The tests are unable to provide a result if the fetal fraction is too low (ie, <4%). The fetal fraction can be affected by maternal and fetal characteristics. For example, the 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 1 in 30 live births in the United States and have a 4- to 10-fold increased risk of perinatal complications. Dizygotic or "fraternal" twins occur from ovulation and fertilization of 2 oocytes, which results in dichorionic placentation and 2 separate placentas. In contrast to dichorionic twins, monochorionic twin pregnancies share their blood supply. Monochorionic 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 dichorionic twins. Up to 15% of monochorionic twin pregnancies are affected by twin-to-twin transfusion syndrome (TTTS), a condition characterized by relative hypovolemia of 1 twin and hypervolemia of the other. According to estimates from live births, TTTS occurs in up to 15% of monochorionic twin pregnancies. In these twin pregnancies, serial fetal ultrasound examinations are necessary to monitor for the 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 fetal cell-free DNA to determine zygosity in twin pregnancies could potentially inform decisions about early surveillance for TTTS and other monochorionic twin-related abnormalities. In particular, determining zygosity with NIPT could potentially assist in the assessment of chorionicity when ultrasound findings are not clear.

Single-Gene Disorders

Single-gene disorders (also known as monogenic disorders) are caused by a variation in a single gene. Individually, single-gene disorders are rare, but collectively are present in approximately 1% of births. The Vistara Single-Gene Disorder Test panel screens for 25 conditions that result from variants across 30 genes, which have a combined incidence of 1 in 600 (0.17%). These include Noonan syndrome and other Noonan spectrum disorders, skeletal disorders (e.g., osteogenesis imperfecta, achondroplasia), craniosynostosis syndromes, Cornelia de Lange syndrome, Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1-related intellectual disability, CHARGE syndrome, Sotos syndrome, and Rett syndrome. The UNITY Fetal Risk Screen™ provides maternal carrier testing for several autosomal recessive conditions (alpha and beta-thalassemia, cystic fibrosis, sickle cell disease, and spinal muscular atrophy) followed by reflex single-gene NIPT of the fetus when a maternal carrier is identified. The clinical presentation and severity of these disorders can vary widely. Some, but not all, can be detected by prenatal ultrasound examination.

Cell-Free Fetal DNA Analysis Methods

Sequencing-based tests use 1 of 2 general approaches to analyzing fetal 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 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 fetal 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 UNITY Fetal Risk Screen™ employs a proprietary molecular counting method called the Quantitative Counting Template to determine the number of input DNA molecules when sequencing. Quantitative counting templates are inserted into the maternal cfDNA specimen, which is designed to co-amplify at the same rate as the corresponding gene of interest and can be used to calculate the number of genes of interest.

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 (eg, 21, 18, and 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 fetal cell-free 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 polymerase chain reaction (PCR) amplification or sequencing. The procedure consists of the digestion of cell-free DNA (cfDNA) using a restriction enzyme. The digested cell-free DNA is then hybridized and ligated to chromosome-specific DNA probes forming a circular DNA. All non-circular DNA is removed by exonuclease treatment. Finally, the circular DNA containing the cfDNA is amplified with rolling circle amplification to form rolling circle products that are labeled with chromosome-specific fluorescently labeled DNA probes. The fluorescently labeled rolling circle products are imaged and counted with an automated microscopy scanner. The microscope takes multiple images from each well with different spectral filters, i.e. each wavelength range presents a specific chromosome. With image analysis algorithms, the fluorescently labeled rolling circle products are counted for each sample. The ratio between the number of chromosome-specific rolling circle products is then transferred to risk calculation software to calculate the likelihood of a trisomy. Currently, Vanadis NIPT provides results for trisomy 21, trisomy 18 and trisomy 13, and fetal sex determination.

Copy Number Variants and Clinical Disorders

Microdeletions (also known as submicroscopic deletions) are 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 long. Along with microduplications, microdeletions are collectively known as copy number variants. Copy number variants can lead to disease when the change in the copy number of a dose-sensitive gene or genes disrupts the ability of the gene(s) to function and affects the amount of protein produced. A number of genomic disorders associated with microdeletion have been identified, which may be associated with serious clinical features, such as cardiac anomalies, immune deficiency, palatal defects, and developmental delay as in DiGeorge syndrome. Some of the syndromes (eg, DiGeorge) have complete penetrance yet marked variability in clinical expressivity. 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. The risk of a fetus with a microdeletion syndrome is independent of maternal age. There are few population-based data and most studies published to date have based estimates on phenotypic presentation. The 22q11.2 (DiGeorge) microdeletion is the most common associated with a clinical syndrome. The table below provides prevalence estimates for the most common microdeletion syndromes. These numbers likely underestimate the prevalence of these syndromes in the prenatal population because the population of variant carriers includes phenotypically normal or very mildly affected individuals.

Recurrent Microdeletion Syndromes

Routine prenatal screening for microdeletion syndromes is not recommended by national organizations. Current practice is to offer invasive prenatal diagnostic testing in select cases to women when a prenatal ultrasound indicates anomalies (eg, heart defects, cleft palate) that could be associated with a particular microdeletion syndrome. For those who do have prenatal screening for microdeletion syndromes, diagnostic testing is necessary to confirm positive results. Diagnostic testing is generally done by chorionic villus sampling (cvs) or amniocentesis. CVS uses placental cells collected for genetic evaluation under ultrasound guidance without entering the amniotic sac. Diagnostic amniocentesis uses a small sample of the fluid that surrounds the fetus, which contains cells that are shed primarily from the fetal skin, bladder, gastrointestinal tract, and amnion. Confined placental mosaicism can cause false-positive cell-free DNA results, and as such, amniocentesis might be preferred over CVS for diagnostic testing in cases of positive cell-free DNA. Both CVS and amniocentesis procedures increase the risk for miscarriage.

Samples are analyzed using fluorescence in situ hybridization, chromosomal microarray analysis, or karyotyping. Additionally, families at risk (eg, those known to have the deletion or with a previously 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.

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 non-invasive prenatal screening tests using fetal cell-free DNA.

Commercially available tests include but are not limited to the following:

• MaterniT®21 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 massive parallel sequencing (MPS) and reports results as positive or negative. The enhanced sequencing series is offered on an opt-out basis.

• Myriad Prequel™ Prenatal Screen (Myriad Women's Health, Counsyl) utilizes whole genome sequencing for detecting aneuploidy including T21, T18, T13.

• 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.

• InformaSeq (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.

• 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.

• PreSeek™ (Baylor Genetics) is a prenatal test which looks at 30 genes for single gene syndromic disorders, skeletal disorders, Noonan spectrum disorders, and craniosynostosis disorders (BRAF, CBL, CDKL5, CHD7, COL1A1, COL1A2, FGFR2, FGFR3, HDAC8, HRAS, JAG1, KRAS, MAP2K1, MAP2K2, MECP2, NIPBL, NRAS, NSD1, PTPN11, RAD21, RIT1, SHOC2, SMC1A, SMC3, SOS1, SOS2, SYNGAP1, TSC1, TSC2).

• QNatal® Advanced (Quest Diagnostics) tests for T21, T18, and T13.

• UNITY Fetal Risk Screen™ (BillionToOne) tests for T21, T18, T13, sex chromosome aneuploidy, fetal sex (optional), fetal RhD status (optional), as well as maternal carrier screening for cystic fibrosis, spinal muscular atrophy, sickle cell disease, alpha and beta-thalassemia, and fragile x syndrome (optional). Fetal screening via single-gene non-invasive prenatal testing is done reflexively for identified maternal carriers. Aneuploidy screening and carrier screening can be ordered independently. The test requires only a maternal blood sample and background information on a priori risk factors to establish a proprietary personalized fetal risk score ranging from >9 in 10 risk to <1 in 20,000 for the recessive condition.

• Vanadis NIPT Solution (PerkinElmer) tests for T21, T18, and T13.

• Veracity® (NIPD Genetics) tests for T21, T18, and T13, sex chromosome aneuploidies, and microdeletions.

• 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.

• VisibiliT (Sequenom Laboratories, now LabCorp) tests for T21 and T18, and tests for sex.

• Vistara™ Single-Gene NIPT tests 25 autosomal dominant and X-linked conditions across 30 genes.

A related medical policy is First-Trimester Detection of Down Syndrome Using Fetal Ultrasound Markers Combined with Maternal Serum Assessment .

POLICY

Nucleic acid sequencing-based testing of maternal plasma to screen for trisomy 21, 18, and 13 may be considered medically necessary in individuals with singleton pregnancies. (Karyotyping would be necessary to exclude the possibility of a false-positive, nucleic acid sequencing–based test. Before testing, individuals should be counseled about the risk of a false-positive test [See Policy Guidelines]).

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 trisomy 21 is considered investigational in individuals with twin or multiple pregnancies.

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.

NIPT of maternal plasma to screen for single-gene disorders (e.g. Vistara or UNITY Fetal Risk Screen™) is considered investigational in all situations.

Nucleic acid sequencing–based testing of maternal plasma, other than in the situations specified above, is considered investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

High-risk singleton pregnancies, as defined by the American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, Number 454, December 2012 include women who meet at least one of the following criteria:

• Maternal age 35 years or older at delivery;

• Fetal ultrasonographic findings indicating increased risk of aneuploidy;

• History of previous pregnancy with a trisomy;

• Standard serum screening test positive for aneuploidy; or

• Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21.

This policy does not apply to pregnancies with a high clinical suspicion of fetal microdeletions for which invasive confirmatory testing is indicated.

In a 2015 committee opinion, the American College of Obstetricians and Gynecologists (ACOG) recommended 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 noninvasive prenatal screening for fetal aneuploidies have reported rare but occasional false-positives. False-positive findings have been found to be associated with factors including placental mosaicism, vanishing twins, and maternal malignancies. Diagnostic testing is necessary to confirm positive cell-free fetal DNA tests, and management decisions should not be based solely on the results of cell-free fetal DNA testing. The ACOG further recommended that individuals with indeterminate or uninterpretable (ie, “no call”) cell-free fetal 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.

Cell-free fetal DNA screening does not assess the risk of neural tube defects. Individuals should continue to be offered ultrasound or maternal serum alpha-fetoprotein screening.

Genetic Counseling

Experts recommend formal genetic counseling for individuals who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some individuals; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Emerging Considerations

Studies on noninvasive prenatal testing (NIPT) for fetal aneuploidy and subchromosomal aberrations have found that this screening method can also incidentally detect maternal malignancies. Findings suggest that unusual or nonreportable NIPT results may be associated with occult maternal cancers, particularly when multiple chromosomal gains and losses are present. Although additional research is needed, whole-body MRI has shown high sensitivity in confirming malignancies in affected individuals. Given these findings, individuals receiving atypical NIPT results may be considered for oncologic evaluation to ensure timely diagnosis and management.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

03/21/2013: Approved by Medical Policy Advisory Committee.

08/01/2013: Added CPT code 81479 to the Code Reference section. Added the following ICD-9 codes to the Code Reference section: 655.10, 655.11, 655.13, 659.50, 659.53, 659.60, 659.63, 758.5, V23.81, and V23.82.

02/18/2014: Added the following new 2014 CPT code(s) to the Code Reference section: 81507.

03/11/2014: Policy reviewed; description updated. Policy statement unchanged.

06/19/2014: Policy reviewed; description updated regarding fetal fraction and general approaches to analyzing cell-free DNA using sequencing-based tests. Policy statement unchanged.

12/31/2014: Added the following new 2015 CPT code to the Code Reference section: 81420.

08/26/2015: Medical policy revised to add ICD-10 codes.

11/13/2015: Policy title changed from "Sequencing-based Tests to Determine Trisomy 21 from Maternal Plasma DNA" to "Noninvasive Prenatal Screening for Fetal Aneuploidies and Microdeletions Using Cell-Free Fetal DNA." Policy description updated regarding microdeletions and available tests. Medically necessary statement regarding nucleic acid sequencing-based testing updated to change "high-risk singleton pregnancies" to "singleton pregnancies." Removed not medically necessary statement regarding women with average-risk singleton pregnancies. Added the following policy statements: 1) 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 21.2) Nucleic acid sequencing–based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above,is considered investigational. Added two policy statements to state that nucleic acid sequencing-based testing of maternal plasmafor fetal sex chromosome aneuploidies and microdeletion are considered investigational. Policy guidelines updated to remove information regarding high-risk singleton pregnancies; added ACOG recommendations and information regarding genetic counseling. Medically necessary and investigative definitions added.

05/27/2016: Policy number A.4.01.21 added.

06/22/2016: Code Reference section updated to add the following ICD-10 diagnosis codes as covered: O09.891, O28.5, Z34.01, Z34.81, and Z36.

11/29/2016: Policy description updated to add section headings. Policy statements unchanged. Policy Guidelines updated to remove information regarding tissue samples by chorionic villous sampling or amniocentesis for karyotyping.

12/30/2016: Code Reference section updated to add new 2017 CPT code 81422.

07/24/2017: Code Reference section updated to add CPT code 81422 to the Investigational Codes table.

09/12/2017: Policy description updated regarding tests. Policy statements unchanged. Policy Guidelines updated regarding standard terminology for variant classification.

09/29/2017: Code Reference section updated to add new ICD-10 diagnosis code Z36.0. Effective 10/01/2017.

06/15/2018: Code Reference section updated to add new CPT code 0060U, effective 07/01/2018.

11/01/2018: Policy description updated regarding fetuses with T18 and T13, as well as recurrent microdeletion syndromes. First policy statement revised to state that nucleic acid sequencing-based testing of maternal plasma to screen for trisomy 21, 18, and 13 may be considered medically necessary in women with singleton pregnancies. Removed second policy statement regarding trisomies 13 and 18. Policy Guidelines updated regarding genetic counseling. Code Reference section updated to add CPT code 0009M as covered. Removed deleted ICD-10 diagnosis code Z36.

09/17/2019: Policy description updated regarding commercially available tests. Policy statements unchanged. Code Reference section updated to add new CPT codes 0124U, 0125U, 0126U, 0127U, and 0128U, effective 10/01/2019.

12/19/2019: Code Reference section updated to make note of deleted CPT code.

03/17/2020: Code Reference section updated to add new CPT code 0168U, effective 04/01/2020.

06/25/2020: Code Reference section updated to make note of deleted CPT codes.

06/30/2021: Code Reference section updated to add new CPT code 0252U, effective 07/01/2021. Removed deleted CPT codes 0009M, 0124U, 0125U, 0126U, 0127U, and 0128U.

09/01/2021: Policy title updated to include "Twin Zygosity." Policy description updated regarding twin zygosity testing, cell-free fetal DNA, and commercially available tests. Added the following policy statements: 1) Nucleic acid sequencing-based testing of maternal plasma for twin zygosity is considered investigational. 2) Vanadis NIPT of maternal plasma to screen for trisomy 21, 18, and 13 is considered investigational in all situations. Policy Guidelines updated to remove genetics nomenclature and to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/09/2021: Policy description updated regarding cell free DNA testing. Policy statements unchanged.

06/27/2022: Code Reference section updated to change "Covered Codes" to "Medically Necessary Codes." Added new CPT code 0327U, effective 07/01/2022.

09/29/2022: Code Reference section updated to add new ICD-10 diagnosis codes O35.10X0, O35.10X1, O35.10X2, O35.10X3, O35.10X4, O35.10X5, O35.10X9, O35.11X0, O35.11X1, O35.11X2, O35.11X3, O35.11X4, O35.11X5, O35.11X9, O35.12X0, O35.12X1, O35.12X2, O35.12X3, O35.12X4, O35.12X5, O35.12X9, O35.13X0, O35.13X1, O35.13X2, O35.13X3, O35.13X4, O35.13X5, O35.13X9, O35.14X0, O35.14X1, O35.14X2, O35.14X3, O35.14X4, O35.14X5, O35.14X9, O35.15X0, O35.15X1, O35.15X2, O35.15X3, O35.15X4, O35.15X5, O35.15X9, O35.19X0, O35.19X1, O35.19X2, O35.19X3, O35.19X4, O35.19X5, and O35.19X9, effective 10/01/2022.

05/01/2023: Policy title changed from "Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, and Twin Zygosity Using Cell-Free Fetal DNA" to "Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, Single-Gene Disorders, and Twin Zygosity Using Cell-Free Fetal DNA." Policy description updated regarding fetal aneuploidy screening, single-gene disorders, recurrent microdeletion syndromes, and commercially available tests. Added policy statement that Vistara NIPT of maternal plasma to screen for single-gene disorders is considered investigational in all situations. Policy Guidelines updated. Code Reference section updated to add CPT code 88271 as investigational. Removed deleted CPT code 0168U.

08/15/2023: Code Reference section updated to add ICD-10 diagnosis codes Z34.00, Z34.02, Z34.03, Z34.80, Z34.82, Z34.83, Z34.90, Z34.91, Z34.92, and Z34.93.

10/04/2023: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals." Code Reference section updated to remove deleted ICD-10 diagnosis codes O35.1XX0, O35.1XX1, O35.1XX2, O35.1XX3, O35.1XX4, O35.1XX5, and O35.1XX9.

06/01/2024: Policy description updated regarding commercially available tests. Investigational policy statement regarding screening for single-gene disorders updated to include UNITY NIPT. Code Reference section updated to add CPT code 0449U as investigational.

10/01/2024: Code Reference section updated to add new CPT codes 0488U and 0489U.

04/18/2025: Policy description updated regarding tests. Investigational statement regarding NIPT of maternal plasma revised to change "UNITY NIPTs" to "UNITY Fetal Risk Screen™." Policy Guidelines updated regarding studies on noninvasive prenatal testing.

SOURCE(S)

Blue Cross Blue Shield Association policy # 4.01.21

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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