Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS) Form

Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation
Revision log

# CONCERT GENETICS GENETIC TESTING: NON-INVASIVE PRENATAL SCREENING (NIPS)

Other common names for this test include: Non-invasive Prenatal Testing (NIPT), Cell-free DNA Testing (cfDNA), Cell-free Fetal DNA Testing (cffDNA)

See [Important Reminder](at the end of this policy for important regulatory and legal information).

## OVERVIEW

Non-invasive prenatal screening (NIPS) is a [sequencing test](performed on placental cell-free DNA found in maternal serum and is most commonly used to screen for fetal aneuploidy (trisomy 21, trisomy 13, and trisomy 18). Sex chromosomes are also screened for fetal sex determination and sex chromosome aneuploidy. NIPS is a screening test and does not provide definitive diagnosis for a fetus. When NIPS is positive, or high risk, for a genetic abnormality, the fetus is at increased risk for that condition. Further testing via karyotype, FISH, or CMA would be necessary to exclude the possibility of a false-positive.

Before testing, guidelines recommend that pregnant people be counseled about the risk of a false-positive result. False-positive findings have been associated with factors, including placental mosaicism, vanishing twin, or a confounding factor within the pregnant person (such as a genetic condition or malignancy).

NIPS has expanded to include microdeletion and microduplication syndromes, as well as single-gene disorders, although this is an area of ongoing research. NIPS has also expanded to predict twin zygosity (i.e., monozygotic versus dizygotic twins). Monozygotic twins have a higher risk for certain complications, such as twin-twin transfusion syndrome (TTTS).

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# POLICY REFERENCE TABLE

## Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT® is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2022, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.

Please see the [Concert Genetics Platform](for a comprehensive list of registered tests.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| Non-invasive Prenatal Screening (NIPS) for Chromosome 13, 18, 21, X and Y Aneuploidies | Vasistera (Natera) | 0327U | O09, O28, O30, O35, Q90-Q99, Z34, Z36.0 | 1, 2, 3, 5 |
| | Panorama Prenatal Panel (with or without twin zygosity testing) (Natera) (twin zygosity only) | 81420, 0060U | | |
| | Singleton NIPS (chromosomes 13, 18, 21) (Invitae) | | | |
| | MaterniT21 PLUS (Integrated Genetics) | | | |
| | Harmony Prenatal Test (BioReference Laboratories ) | 81507 | | |
| Non-invasive Prenatal Screening (NIPS) for Microdeletions | Panorama Extended Panel (Natera) | 81422, 0060U (twin zygosity only) | O09, O28, O35, Q90-Q99, Z34, Z36.0 | 3, 5, 6 |
| | MaterniT21 Plus Core + ESS (Integrated Genetics) | | | |
| | Prequel Prenatal Screen: Microdeletions (Myriad) | | | |
| Non-invasive Prenatal Screening (NIPS) for Single-Gene Disorders | Vistara (Single-Gene NIPT) (Natera) | 81302, 81404, 81405, 81406, 81407, 81408, 81442 | O09, O28, O30, O35, Q90-Q99, Z34, Z36.0 | 4 |
| | PreSeek Non-invasive Prenatal Gene Sequencing Screen (Baylor Miraca Genetics Laboratories) | | | |
| Maternal Serum Screening (MSS) | First Trimester Screen, hCG (Quest Diagnostics) | 81508 | | 3 |
| | Quad Screen (Quest Diagnostics) | 81509, 81510, 81511, 81512 | O09, O28, O30, O35, Q90-Q99, Z34, Z36.0 | |
| | Serum Integrated Screen, Part 2 (Quest Diagnostics) | | | |
| | Penta Screen (Quest Diagnostics) | 81512 | | |

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# OTHER RELATED POLICIES

This policy document provides criteria for Non-Invasive Prenatal Screening (NIPS). Please refer to:

- **Oncology: Circulating Tumor DNA and Circulating Tumor Cells (Liquid Biopsy)** for criteria related to circulating tumor DNA (ctDNA) or circulating tumor cell testing performed on peripheral blood for cancer diagnosis, management and surveillance.
- **Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy Loss** for coverage related to prenatal and pregnancy loss diagnostic genetic testing.
- **Genetic Testing: Prenatal and Preconception Carrier Screening** for criteria related to carrier screening for genetic disorders.
- **Genetic Testing: Preimplantation Genetic Testing** for criteria related to genetic testing of embryos prior to in vitro fertilization.
- **Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay** for criteria related to diagnostic genetic testing in the postnatal period.
- **Genetic Testing: General Approach to Genetic and Molecular Testing** for criteria related to non-invasive prenatal screening that is not specifically discussed in this or other non-general policies.

# CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is **medically necessary** when meeting the related criteria:

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# Non-invasive Prenatal Screening (NIPS) for Chromosome 13, 18, 21, X and Y Aneuploidies

I. Noninvasive Prenatal Screening (NIPS) for 13, 18, 21, X and Y aneuploidy (81420, 81507, 0327U) may be considered **medically necessary** when:
    A. The member/enrollee has a singleton or twin pregnancy, AND
    B. The member/enrollee has NOT previously had cell-free DNA screening in the current pregnancy

II. NIPS to predict [twin zygosity](0060U) is considered **investigational**.

III. NIPS is considered **investigational** for all other indications, including the following:
    A. For all other aneuploidies (other than trisomy 13, 18, and 21)
    B. For multiple gestation pregnancies (triplets or higher)
    C. NIPS performed simultaneously with maternal serum screening
    D. Use on a singleton pregnancy with a known vanishing twin
    E. For the sole purpose of fetal sex determination

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# Non-invasive Prenatal Screening (NIPS) for Microdeletions

I. NIPS for microdeletion and microduplications (81422, 0060U) is considered **investigational**.

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# Non-invasive Prenatal Screening (NIPS) for Single-gene Disorders

I. NIPS for mutations associated with single gene disorders (81302, 81404, 81405, 81406, 81407, 81408, 81442) is considered **investigational**.

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# Maternal Serum Screening (MSS)

I. Maternal serum screening for aneuploidy using no more than one of the following one time per pregnancy is considered **medically necessary**:
    A. First trimester screening (free or total beta-HCG and PAPP-A) (81508)
    B. Second trimester screening (hCG, msAFP, uE3, and DIA) (81509, 81510, 81511, 81512)
    C. Integrated, stepwise sequential, or contingent sequential screening (81508, 81509, 81510, 81511, 81512)
    D. Penta screen (hCG, msAFP, uE3, DIA, ITA) (81512)

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# NOTES AND DEFINITIONS

1. Noninvasive prenatal screening (NIPS) is a screening test that is used to determine the risk of specific genetic disorders by analyzing traces of cell-free DNA (cfDNA) in a pregnant woman’s blood.
2. Sequencing-based tests use 1 of 2 general approaches to analyze cell-free DNA. The most widely used technique to date uses massively parallel sequencing (MPS; also known as next-generation or “next gen” sequencing). The second general approach uses the single nucleotide polymorphism (SNP) method.
3. Singleton pregnancy is a pregnancy with one fetus.
4. Twin Zygosity testing is used to predict the degree of genetic similarity within each pair (i.e., monozygotic versus dizygotic). Monozygotic (genetically identical twins) are at a higher risk for pregnancy complications, such as twin-twin transfusion syndrome (TTTS).

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# BACKGROUND AND RATIONALE

## Non-invasive Prenatal Screening (NIPS) for Chromosome 13, 18, 21, X and Y Aneuploidy

### American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM)

ACOG and SMFM (2020) released a joint practice bulletin (No. 226) with the following recommendations for screening for fetal chromosomal abnormalities:

The following recommendations and conclusions are based on good and consistent scientific evidence (Level A):
- Cell-free DNA is the most sensitive and specific screening test for the common fetal aneuploidies. Nevertheless, it has the potential for false-positive and false-negative results. Furthermore, cell-free DNA testing is not equivalent to diagnostic testing. (p. e63)

The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B):
- Cell-free DNA screening can be performed in twin pregnancies. Overall, performance of screening for trisomy 21 by cell-free DNA in twin pregnancies is encouraging, but the total number of reported affected cases is small. Given the small number of affected cases it is difficult to determine an accurate detection rate for trisomy 18 and 13. (p. e64)

Regarding prenatal screening for multiple gestation pregnancies of triplets or higher, Practice Bulletin No. 226 also states: “…there are no data available for serum screening for higher-order multiple gestations such as triplets and quadruplets.” (p. e59)

Regarding screening a pregnancy with a vanishing twin: “In a patient with both a vanishing twin and a viable intrauterine pregnancy, cell-free DNA screening is not advised because of the high risk for aneuploidy in the nonviable sac or embryo, which can lead to false-positive results.” (p. e53)

The Practice Bulletin No. 226 also notes that “[i]f screening is accepted, patients should have one prenatal screening approach, and should not have multiple screening tests performed simultaneously.” (p. e49)

### American College of Medical Genetics and Genomics (ACMG)

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

ACMG (2016) published a position statement on noninvasive prenatal screening (NIPS) for fetal aneuploidy.

ACMG recommends:
- Informing all pregnant women that NIPS is the most sensitive screening option for traditionally screened aneuploidies (i.e., T13, T18, and T21). (page 1059)
- Referring patients to a trained genetics professional when an increased risk of aneuploidy is reported after NIPS. (page 1059)
- Providers should make efforts to deter patients from selecting sex chromosome aneuploidy screening for the sole purpose of biologic sex identification in the absence of a clinical indication for this screening. (p. 1060)

Current ACMG practice guidelines (2022) “strongly recommends NIPS over traditional screening for all pregnant patients with singleton and twin gestations for fetal trisomies 21, 18, and 13 and strongly recommends NIPS be offered to patients to screen for fetal sex chromosome aneuploidy.” (p. 1 and p. 5)

### National Society for Genetic Counselors (NSGC)

The National Society for Genetic Counselors adopted the following statement updated in 2021 supporting prenatal cell-free DNA (cfDNA) screening as an option for pregnant patients:

The National Risk of Genetic Counselors believes that all pregnant patients, regardless of aneuploidy risk, should have access to prenatal aneuploidy screening using cell-free DNA (cfDNA)*. Healthcare providers should present cfDNA screening for aneuploidy within the context of other available prenatal screening and diagnostic testing options. Included in this discussion should be the option of pursuing diagnostic testing as a first line approach or declining all screening/testing. Pretest counseling should also include a discussion of the individual patient’s values, preferences, and needs, as well as the benefits and limitations of cfDNA screening. Many factors influence cfDNA screening performance; therefore, it may not be appropriate for every clinical scenario. Additionally, some laboratories offer screening for conditions beyond common aneuploidies, so it is essential to consider the test’s positive predictive value, particularly when the prevalence of the disorder is low.

Patients who receive increased risk or inconclusive/atypical results should receive post-test genetic counseling with a knowledgeable healthcare provider, such as a genetic counselor. In such cases, confirmatory diagnostic testing may be indicated, and patients should be counseled that no irreversible actions should be taken based on the cfDNA screening alone.

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# Non-invasive Prenatal Screening (NIPS) for Microdeletions

### American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM)

ACOG and SMFM (2020) released a joint practice bulletin (No. 226) with the following recommendations for screening for fetal chromosomal abnormalities:

Screening for a limited number of microdeletions with cell-free DNA is available; however, this testing has not been validated clinically and is not recommended. Although microdeletions are relatively common when considered in aggregate, cell-free DNA panels only include a few specific clinically significant microdeletions and these are very rare. Therefore, the PPV for these disorders is much lower than for common trisomies. (p. e53)

### American College of Medical Genetics (ACMG)

The ACMG practice guideline from 2023 includes a conditional recommendation, suggesting 22q11.2 deletion syndrome be offered to all patients. The guideline defines a conditional recommendation as follows: “most patients would request this testing and most clinicians would offer NIPS for this purpose, after a discussion about the benefits and limitations of screening and in the context of shared-decision making.” (p. 19)

Furthermore, the ACMG statement discusses a study (Dar, et al, 2022) that assessed the performance of SNP-based NGS and included more than 18,000 subjects. Results of the analysis demonstrated a 0.05% false positive rate and a 52.6% positive predictive value. (pages 5-6). Specifically, the study quoted a positive predictive value of 21% for DiGeorge syndrome. (Petersen, et al 2017, p. 691.e1 and e4). However, studies attempting to validate the clinical utility of microdeletion analysis via NIPS have overall shown low positive predictive values and higher false positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population.

At the present time, testing for microdeletions, including 22q11.2, via non-invasive prenatal screening has insufficient evidence in peer-reviewed publications to effectively result in improved health outcomes compared to the current standard of care. Further studies are needed to determine the sensitivity and specificity of the test.

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# Non-invasive Prenatal Screening (NIPS) for Single Gene Disorders

### The American College of Obstetricians and Gynecologists (ACOG)

ACOG issued a practice advisory for the use of cell-free DNA to screen for single-gene disorders (February 2019, reaffirmed October 2022), which states the following:

The continued innovation in cell-free technology combined with the desire for a maternal blood test to predict the risk for fetal genetic disorders during a pregnancy has broadened the application of cell-free DNA screening beyond aneuploidy to single-gene disorders. Examples of single-gene disorders include various skeletal dysplasias, sickle cell disease and cystic fibrosis. Although this technology is available clinically and marketed as a single-gene disorder prenatal screening option for obstetric care providers to consider in their practice, often in presence of advanced paternal age, there has not been sufficient data to provide information regarding accuracy and positive and negative predictive value in the general population. For this reason, single-gene cell-free DNA screening is not currently recommended in pregnancy.

### Maternal Serum Screening

#### The American College of Obstetricians and Gynecologists (ACOG)

The American College of Obstetricians and Gynecologists (ACOG) provided an updated position statement (number 226) regarding Screening for Fetal Chromosomal Abnormalities.

Specifically, these guidelines state: “Prenatal genetic screening (serum screening with or without nuchal translucency [NT] ultrasound or cell-free DNA screening) and diagnostic testing (chorionic villus sampling [CVS] or amniocentesis] options should be discussed and offered to all pregnant women regardless of chromosomal age or risk of chromosomal abnormality.” (p. 862)

The use of multiple screening approaches performed independently (e.g., a first-trimester screening test followed by a quad screen as an unlinked test) is not recommended because it will result in an unacceptably high positive screening rate and could deliver contradictory results. (p. 865)

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Concert Genetics Genetic Testing: Non-invasive Prenatal Screening (NIPS)
V1.2024
Date of Last Revision: 10/1/2023
CENTENE Corporation

# Reviews, Revisions, and Approvals

| Policy developed | Revision Date | Approval Date |
|------------------|--------------|--------------|
| Policy developed. | 03/23 | 03/23 |
| Semi-annual review. Updated title to reflect V1.2024 version. Overview, coding, reference-table, background and references updated. Throughout policy: replaced “coverage criteria” with “criteria”. For Overview: added “via karyotype, FISH, or CMA”; added “Before testing, guidelines recommend…”; removed “recently”. For Policy Reference Table: under Non-invasive Prenatal Screening (NIPS) for Chromosome 13, 18, 21, X and Y Aneuploidies added “with or without twin zygosity testing”; added “twin zygosity only”; added “Prenatal Test”; under Non-invasive Prenatal Screening (NIPS) for Microdeletions replaced “with microdeletion syndromes” with “(Extended Panel)”; removed “81420”; added “twin zygosity only”; under Non-invasive Prenatal Screening (NIPS) for Single-Gene Disorders added “and Molecular”. For Other Related Policies: added “and Molecular”. For Criteria: Non-invasive Prenatal Screening (NIPS) for Chromosome 13, 18, 21, X and Y Aneuploidies: added “removed appropriate counseling…”; added “I. removed “trisomy”; under I.B. removed “received cell-free DNA…”; under III. Added “B. For multiple gestation pregnancies…”. For Background and Rationale: added “American College of Medical Genetics (ACMG)…”. under Non-invasive Prenatal Screening (NIPS) for Single Gene Disorders: replaced “March 2020” with “October 2022”; under Maternal Serum Screening: removed “All women should be offered…”; added “The American College of Obstetricians…”. | 10/23 | 10/23 |

  

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