BlueCross BlueShield of Tennessee Medical Policy Manual

Non-invasive Prenatal Testing Using Cell-free Fetal DNA (cffDNA)

DESCRIPTION

Circulating cell-free fetal DNA (ccfDNA) crosses the placenta and can be isolated in maternal plasma. As early as 8-10 weeks of gestation these fetal DNA fragments can comprise 6-10% of the total cell free DNA in maternal plasma. Laboratories have developed tests that analyze cffDNA as a non-invasive screening tool for detecting fetal chromosomal abnormalities such as trisomy 21 (Down Syndrome), trisomy 18 (Edward Syndrome), and trisomy 13 (Patau Syndrome). Examples of commercially available test kits include, but are not limited to:

Some of these tests have also been investigated for the use in detecting sex-linked abnormalities such as Turner Syndrome (XO in females) and Klinefelter Syndrome (XXX or XXY in males). Laboratories have also explored the potential for identifying fetal Rh status using the cell-free fetal DNA technology (e.g., SensiGene®, SEQureDX®).

Cell-free fetal DNA analysis includes sequencing-based tests and single nucleotide variant-based methods. Sequencing-based tests use one of two general approaches to analyzing cell-free fetal DNA. The first category of tests uses quantitative or counting methods. The most widely used technique to date uses 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. Another technique is direct DNA analysis, which analyzes specific cell-free fetal DNA fragments across samples.

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 molecule 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.

Single-gene disorders (also known as monogenic disorders) are caused by a variation in a single gene. They are rare, but jointly are present in approximately 1% of births. The clinical presentation and severity of these disorders can vary extensively and some, not all, can be detected by prenatal ultrasound. The Vistara Single-Gene Disorder Test is being proposed as a screening tool that screens for 25 conditions, resulting from variants across 30 genes (i.e., Noonan syndrome & other Noonan spectrum disorders, skeletal disorder (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). It is unclear if Vistara is intended to replace other screening modalities such as ultrasound, or an add-on test. Clinical decision making based on the Vistara NIPT is not well defined.

POLICY

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) to detect fetal aneuploidy is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) when karyotyping, aneuploidy FISH, and/or array-comparative genomic hybridization have already been performed during the current pregnancy is not medically necessary.

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) for the detection of other conditions including, but not limited to the following is considered investigational:

• • Fetal sex chromosome aneuploidies (e.g., Turner Syndrome, Klinefelter Syndrome)

  • To determine fetal RHD genotyping

  • Microdeletions (e.g., DiGeorge syndrome, Prader-Willi syndrome, Angelman syndrome, 1p36 deletion syndrome, Cri-du-chat syndrome, Wolf-Hirschhorn, Miller-Dieker)

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) to screen for trisomy 21, 18 and 13 using a test that does not involve sequencing or amplification (e.g., Vanadis) is considered investigational in all situations.

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) to screen for single-gene disorders (e.g., Vistara) is considered investigational in all situations.

MEDICAL APPROPRIATENESS

• Non-invasive prenatal testing of maternal plasma using cell-free fetal DNA (cffDNA) is considered medically appropriate if ALL of the following criteria are met:

• • Singleton pregnancy

  • One (1) test per pregnancy, even if the first test was inconclusive

  • Sequencing-based or single nucleotide variant-based method is used

  • Test is done no sooner than 10 weeks gestation

  • Testing is indicated to determine presence of ANY ONE of the following chromosomal abnormalities:

  • • Trisomy 21 - Down Syndrome

    • Trisomy 18 - Edward Syndrome

    • Trisomy 13 - Patau Syndrome

IMPORTANT REMINDERS

• Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.

• We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the medical policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

ADDITIONAL INFORMATION

There is insufficient evidence that noninvasive prenatal testing using cell-free fetal DNA is accurate for detecting fetal aneuploidy in twin and multiple pregnancies and using a testing method that does not involve sequencing or amplification. The clinical utility of early sex chromosome aneuploidy detection is also unclear.

SOURCES

American College of Medical Genetics and Genomics (ACMG). (2023) Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline. Retrieved November 9, 2023 from http://www.acmg.net.

American College of Obstetricians and Gynecologists, Committee on Genetics; Society of Maternal-Fetal Medicine. (2016, May; reaffirmed 2020). Practice bulletin number 226: Screening for fetal chromosomal abnormalities. Retrieved November 13, 2023 from http://www.acog.org.

American College of Obstetricians and Gynecologists, Committee on Practice Bulletins - Obstetrics. (2017, August). Practice bulletin number 181: Prevention of Rh D alloimmuninization. Retrieved August 30, 2022 from http://www.acog.org.

American College of Obstetricians and Gynecologists, Practice Advisory. (2019, February; reaffirmed 2021). Cell-free DNA to screen for single-gene disorders. Retrieved August 30, 2022 from http://www.acog.org.

Bianchi, D., Parker, L., Wentworth, J., Madankumar, R., Saffer, C., Das, A., et al. (2014). DNA sequencing versus standard prenatal aneuploidy screening. The New England Journal of Medicine. Vol. 370, (9), 800-808. (Level 2 evidence)

BlueCross BlueShield Association. Evidence Positioning System (9:2023). Noninvasive fetal RhD genotyping using cell-free fetal DNA. (2.04.108). Retrieved November 9, 2023 from https://www.bcbsaoca.com/eps/. (13 articles and/or guidelines reviewed)

BlueCross BlueShield Association. Evidence Positioning System. (9:2023). Noninvasive prenatal screening for fetal aneuploidies, microdeletions, and twin zygosity using cell-free fetal DNA. (4.01.21). Retrieved November 9, 2023 from https://www.bcbsaoca.com/eps/. (32 articles and/or guidelines reviewed)

Bussolaro, S., Raymond, Y. C., Acreman, M. L., Guido, M., Da Silva Costa, F., Rolnik, D. L., et al. (2023). The accuracy of prenatal cell-free DNA screening for sex chromosome abnormalities: A systematic review and meta-analysis. American Journal of Obstetrics & Gynecology MFM, 5 (3), 100844. Abstract retrieved November 10, 2023 from PubMed database.

Dondorp, W., de Wert, G., Bombard, Y., Bianchi, D., Bergmann, C., Borry, P., et al. (2015). Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. European Journal of Human Genetics, 23, 1438-1450. (Level 5 evidence)

Gil, M., Accurti, V., Santa Cruz, B., Plana, M., & Nicholaides, K. (2017). Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstetrical Gynecology, 50, 302-314. (Level 2 evidence)

Li, W., Wang, P., Chuang, C., Chang, Y., Yang, M., Chen, C. et al. (2015). Noninvasive prenatal testing for fetal trisomy in a mixed risk factors pregnancy population. Taiwanese Journal of Obstetrics & Gynecology, 54,122-125. (Level 4 evidence)

National Institute for Health and Clinical Evidence (NICE). (2016, November). High-throughput non-invasive prenatal testing for fetal RHD genotyping. Retrieved July 12, 2021 from http://www.nice.org.uk.

Norton, M., Jocobsson, B., Swamy, G., Laurent, L., Ranzini, A., Brar, H., et al. (2015). Cell-free DNA analysis for noninvasive examination of trisomy. The New England Journal of Medicine, 372 (17), 1589-1597. (Level 2 evidence)

Runkel, B., Bein, G., Sieben, W., Sow, D., Polus, S., & Fleer, D. (2020). Targeted antenatal anti-D prophylaxis for RhD-negative pregnant women: a systematic review. BMC Pregnancy Childbirth, 20 (83), doi: 10.1186/s12884-020-2742-4. (Level 2 evidence)

Taylor-Phillips, S., Freeman, K., Geppert, J., Agbebiyi, A., Uthman, O., Madan, J., et al. (2015). Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. British Medical Journal (BMJ) 6:e010002. (Level 1 evidence)

Zaninović, L., Bašković, M., Ježek, D., & Katušić Bojanac, A. (2022). Validity and utility of non-invasive prenatal testing for copy number variations and microdeletions: a systematic review. Journal of Clinical Medicine, 11 (12), 3350. (Level 1 evidence)

ORIGINAL EFFECTIVE DATE:  6/8/2013

MOST RECENT REVIEW DATE:  12/14/2023

ID_BT

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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