MP-06 Cell-Free DNA Testing for Fetal Trisomy Form

Medical Policy

Cell-Free Fetal DNA Testing

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Policy Number: MP-06 Current Effective Date: 04/26/2022 Original Effective Date: 01/01/2016 Next Review/Revision Date: 04/26/2024 Plans: QUEST Integration (Medicaid)

I. Purpose 1.1 The purpose of this policy is to define medically necessary indications of non-invasive prenatal testing (NIPT) for fetal trisomy using cell-free fetal Deoxyribonucleic Acid (cffDNA) in the maternal blood during pregnancy. It is the intent of this policy to recognize cffDNA testing as appropriate and consistent with good medical practice when performed for the indications listed in this policy.

2. Policy 2.1 The American College of Obstetricians and Gynecologists (ACOG) establishes the standard care of obstetric practice in the US. ACOG recommends that pregnant mothers of advanced age (≥35) be offered prenatal screening and/or diagnostic testing for chromosomal aneuploidies. Definitive prenatal diagnosis requires invasive sampling of fetal DNA through amniocentesis and chorionic villus sampling (CVS), with a risk (albeit low) for the fetus.7.7, 7.16 NIPT is offered as a screening method to well-informed pregnant mothers prior to undergoing invasive diagnostic testing. Pregnant mothers who have negative results on the screening test can avoid invasive, definitive testing. A positive result on the screening test requires confirmation using definitive testing.

   2.2 NIPT using cffDNA to detect the common aneuploidies (trisomy 21, trisomy 18, and trisomy 13) is considered a medically necessary alternative option for pregnant women who have been adequately counseled and desire information on their risk of potential fetal aneuploidy. Evaluation of cffDNA for fetal genetic abnormalities have shown in recent studies to outperform conventional non- invasive prenatal screening in high-risk pregnancies. In patients with reportable results, trisomy 21, trisomy 18, and trisomy 13 sensitivity rates exceed 99%, 97%, and 95% with specificity rates of 99.9%, 99.9%, and 99.8% respectively.7.4

   2.3 Prenatal screening and diagnosis involve clinically uncertain and/or complicated findings using genetic technology. Comprehensive patient pretest and posttest genetic counseling from an obstetrician-gynecologist or other health care provider with genetics expertise regarding the benefits, limitations, and results of cffDNA testing is essential.7.1, 7.7, 7.8

3. Definitions 3.1 Amniocentesis – a prenatal test that can diagnose certain defects and genetic conditions in the fetus. The test is performed between 15 and 20 weeks of the pregnancy, where amniotic fluid is removed from the uterus using a needle inserted through the abdomen.

   3.2 Aneuploidy – an abnormal number of chromosomes (gain or loss) due to an error during cell division.

Medical Policy

Cell-Free Fetal DNA Testing

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3.3 Cell-Free Fetal DNA testing (cffDNA) – a prenatal test that can diagnose certain genetic conditions in the fetus where fetal DNA is collected from maternal blood for evaluation.

3.4 Chorionic villus sampling (CVS) – a prenatal test that can diagnose certain defects and genetic conditions in the fetus. The test is performed between 10 and 13 weeks, a sample of placenta (chorionic villus) is removed through either the abdomen or cervix.

3.5 Maternal – term used to refer to a pregnant woman.

3.6 Non-invasive Prenatal Testing (NIPT) – A screening method where a sample of maternal blood is collected to evaluate or detect genetic abnormalities of a fetus.

3.7 Robertsonian Translocation – a specific translocation of two acrocentric chromosomes, resulting in the fusion of the long q arms. A carrier of a Robertsonian translocation has 45 total chromosomes, 44 normal and one which is the fusion product.

3.8 Trisomy 21 (Down’s Syndrome) – the aneuploidy condition of having an extra copy of chromosome 21, associated with mild to moderate intellectual disability, a characteristic facial appearance, and hypotonia.

3.9 Trisomy 18 (Edwards Syndrome) – the aneuploidy condition of having an extra copy of chromosome 18, associated with severe intellectual disability and physical abnormalities including intrauterine growth retardation (IUGR) and low birth weight.

3.10 Trisomy 13 (Patau Syndrome) – the aneuploidy condition of having an extra copy of chromosome 13, associated with heart defects, brain or spinal cord abnormalities, microphthalmia, extra fingers or toes, cleft lip with or without cleft palate, and hypotonia.

4. Procedure 4.1 Cell-free fetal DNA testing for trisomy 21, trisomy 18, and trisomy 13 is covered in singleton pregnancies who have been identified as high risk by any of the following. Prior authorization with documentation is required for determination of medical necessity. a. Patient will be 35 years old or over at estimated date of delivery; b. Fetus with one or more major structural abnormalities identified on ultrasonographic findings; c. Patient has a history of prior pregnancy with a trisomy; d. Standard serum screening test positive for aneuploidy; or e. Either parent has a balanced Robertsonian translocation leading to an increased risk of fetal trisomy 13 or trisomy 21.

5. Limitations 5.1 While cffDNA has been proven to have high sensitivity and specificity, cffDNA has a low positive predictive value (PPV) in normal risk pregnancies.7.3, 7.4, 7.5, 7.11 The Cochrane Collaboration (2017) concluded that, “with respect to the replacement of invasive tests, the performance of NIPT is not sufficient to replace current invasive diagnostic test” in a population of unselected pregnant individuals. Thus, this test is appropriate only to screen high risk pregnant patients, as defined above.

Medical Policy

Cell-Free Fetal DNA Testing

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5.2 As cffDNA is a screen and not a diagnostic test, pregnant patients with observation of fetal structural anomalies on ultrasound should be offered conventional diagnostic testing rather than cffDNA. In addition, patients with an abnormal result from cffDNA testing must have an amniocentesis or CVS for diagnostic confirmation.7.3, 7.4, 7.7

5.3 The following is considered not medically necessary and will not be covered. a. NIPT performed in place of conventional diagnostic testing (i.e. without confirmation by conventional testing methods); b. Patients with multiple gestations (e.g. twins, triplets, etc.); c. Low-risk or average-risk pregnancy; d. Evaluation of sex chromosome abnormalities; e. NIPT to determine biologic sex; f. Evaluation of microdeletions or micro-duplication syndromes; g. Evaluation of neural tube defect or ventral wall defects; or h. When a fetal structure anomaly has been identified on ultrasound examination.

5.4 In accordance with the American Medical Association (AMA) 2019 HCPCS/CPT guidelines, do not report 81228, 81229 and 88271 when performing genomic sequencing procedures or other molecular multianalyte assays for copy number analysis. See HCPCS/CPT Code 81507 below.

6. Coding Information The following medical codes are relevant codes for diagnosis and procedures for Cell-Free Fetal DNA Testing for fetal trisomy and for informational purposes only. All the medical codes listed in this policy do not constitute or imply benefit coverage or provider reimbursement. ICD‐10‐CM Covered Description O09.291-O09.299 Supervision of pregnancy with other poor reproductive or obstetric history O09.511-O09.519 Supervision of elderly primigravida O09.521-O09.529 Supervision of elderly multigravida O35.1XX0 Maternal care for (suspected) chromosomal abnormality in fetus [aneuploidy in mother, fetal aneuploidy] Q95.0-Q95.9 Balanced rearrangements and structural markers, not elsewhere classified. Includes Robertsonian and balanced reciprocal translocations and insertions

   ICD-10-CM Not Covered: Description O28.0-O28.9 Abnormal finding on antenatal screening of mother Q92.0-Q92.9 Other trisomies and partial trisomies of the autosomes, not elsewhere classified Q93.88 Other microdeletions [micro-deletion syndrome] Z13.228 Encounter for screening for other metabolic disorders [not covered for use of urinary markers (measurement of cell free DNA and metabolomic profiling) for testing for fetal

Medical Policy

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aneuploidy (trisomy 21,18,13) in pregnant women] Z13.71-Z13.79 Encounter for screening for genetic and chromosomal anomalies. Z31.438 Encounter for other genetic testing of female for procreative management Z34.80-Z34.93 Encounter for supervision of normal pregnancy [low risk women]

HCPCS/CPT Covered Description 81420 Fetal chromosomal aneuploidy (e.g., trisomy 21) genomic sequence analysis panel, circulating cell‐free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18, and 21. 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. Do not report 81228, 81229 AND 88271 when performing genomic sequencing procedures or other molecular multianalyte assays for copy number analysis.

HCPCS/CPT Not Covered: Description 0060U Twin zygosity, genomic targeted sequence analysis of chromosome 2, using circulating cell-free DNA in maternal blood

7. References/Resources 7.1 American College of Obstetricians and Gynecologists (ACOG). Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Committee Opinion NO: 682. Obstet Gynecol. 2016;128:e262-8. 7.2 American College of Obstetricians and Gynecologists (ACOG). Ethical Issues in Genetic Testing. Committee Opinion NO: 410. Obstet Gynecol. 2008 (Reaffirmed 2014); 111:1495-502. 7.3 Amorim Costa C. Non-invasive prenatal screening for chromosomal abnormalities using circulating cell-free fetal DNA in maternal plasma: current applications, limitations and prospects. Egypt J Med Hum Genet. 2017;18(1):1-7. 7.4 Badeau M, Lindsay C, et al. Genomics-based non-invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women. Cochrane Database Syst Rev. 2017 Nov 10;11:CD011767. Doi: 10.1002/14651858.CD011767.pub2. 7.5 Bianchi DW, Parker RL, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014; 370:799-808. 7.6 Chitty LS, Hudgins L, et al. Current controversies in prenatal diagnosis 2: Cell-free D prenatal screening should be used to identify all chromosomes abnormalities. Prenatal Diagn. 2018 Feb;38(3):160-165. 7.7 Devers P, Cronister A, et al. Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis: the Position of the National society of Genetic Counselors. Journal of Genetic Counseling. 2013:22(3). 7.8 Gregg AR, Skotko BG, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genetics in

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Medicine. 2016:18(1056-1065). 7.9 Iwarsson E, Jacobsson B, 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. 2017 Jan;96(1):7-18. 7.10 Norton ME et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015;372(17):1589-97. 7.11 Sparks AB, Wang ET, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenatal Diagnosis. 2012. 32(3-9). 7.12 National Institutes of Health, National Library of Medicine. Genetics Home Reference, Trisomy 13, Reviewed November 2013. Accessed: 07/01/2019. 7.13 National Institute of Health, National Library of Medicine. Genetics Home Reference, Trisomy 18, Reviewed March 2012. Accessed 07/01/2019. 7.14 National Institute of Health, National Library of Medicine. Genetics Home Reference, Down syndrome, Reviewed June 2012. Accessed 07/01/2019. 7.15 Taylor-Phillips S, Freeman K, eta al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta- analysis. BMJ Open. 2016 Jan 18;6(1):e010002. 7.16 Zhang H, Gao Y, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound in Obstet Gynecol. 2015 Jan. Vol 45:5:590-

539. Review/Revision Date: 04/26/2024 - Retired