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Prenatal Testing using Cell-free DNA 2024-03-17

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Status: Revised Effective Date: 03/17/2024

Doc ID: GEN04-0324.1 Last Review Date: 07/18/2023

Approval and implementation dates for specific health plans may vary. Please consult the applicable health plan for more details.

Clinical Appropriateness Guidelines

Genetic Testing

Appropriate Use Criteria: Prenatal Testing using Cell-free DNA

Proprietary

© 2024 Carelon Medical Benefits Management, Inc. All rights reserved.

Table of Contents

Description and Application of the Guidelines

General Clinical Guideline

Clinical Appropriateness Framework

Simultaneous Ordering of Multiple Diagnostic or Therapeutic Interventions

Repeat Diagnostic Intervention

Repeat Therapeutic Intervention

Prenatal Testing using Cell-free DNA

Description and Scope

General Recommendations

Clinical Indications

General Requirements

Condition-Specific Requirements

References

Codes

History

Description and Application of the Guidelines

The Carelon Clinical Appropriateness Guidelines (hereinafter “the Carelon Clinical Appropriateness Guidelines” or the “Guidelines”) are designed to assist providers in making the most appropriate treatment decision for a specific clinical condition for an individual. The Guidelines establish objective and evidence-based criteria for medical necessity determinations, where possible, that can be used in support of the following:

  • To establish criteria for when services are medically necessary
  • To assist the practitioner as an educational tool
  • To encourage standardization of medical practice patterns
  • To curtail the performance of inappropriate and/or duplicate services
  • To address patient safety concerns
  • To enhance the quality of health care
  • To promote the most efficient and cost-effective use of services

The Carelon guideline development process complies with applicable accreditation and legal standards, including the requirement that the Guidelines be developed with involvement from appropriate providers with current clinical expertise relevant to the Guidelines under review and be based on the most up-to-date clinical principles and best practices. Resources reviewed include widely used treatment guidelines, randomized controlled trials or prospective cohort studies, and large systematic reviews or meta-analyses. Carelon reviews all of its Guidelines at least annually.

Carelon makes its Guidelines publicly available on its website. Copies of the Guidelines are also available upon oral or written request. Additional details, such as summaries of evidence, a list of the sources of evidence, and an explanation of the rationale that supports the adoption of the Guidelines, are included in each guideline document.

Although the Guidelines are publicly available, Carelon considers the Guidelines to be important, proprietary information of Carelon, which cannot be sold, assigned, leased, licensed, reproduced or distributed without the written consent of Carelon.

Carelon applies objective and evidence-based criteria, and takes individual circumstances and the local delivery system into account when determining the medical appropriateness of health care services. The Carelon Guidelines are just guidelines for the provision of specialty health services. These criteria are designed to guide both providers and reviewers to the most appropriate services based on a patient’s unique circumstances. In all cases, clinical judgment consistent with the standards of good medical practice should be used when applying the Guidelines. Guideline determinations are made based on the information provided at the time of the request. It is expected that medical necessity decisions may change as new information is provided or based on unique aspects of the patient’s condition. The treating clinician has final authority and responsibility for treatment decisions regarding the care of the patient and for justifying and demonstrating the existence of medical necessity for the requested service. The Guidelines are not a substitute for the experience and judgment of a physician or other health care professionals. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment.

The Guidelines do not address coverage, benefit or other plan specific issues. Applicable federal and state coverage mandates take precedence over these clinical guidelines, and in the case of reviews for Medicare Advantage Plans, the Guidelines are only applied where there are not fully established CMS criteria. If requested by a health plan, Carelon will review requests based on health plan medical policy/guidelines in lieu of the Carelon Guidelines. Pharmaceuticals, radiotracers, or medical devices used in any of the diagnostic or therapeutic interventions listed in the Guidelines must be FDA approved or conditionally approved for the intended use. However, use of an FDA approved or conditionally approved product does not constitute medical necessity or guarantee reimbursement by the respective health plan.

The Guidelines may also be used by the health plan or by Carelon for purposes of provider education, or to review the medical necessity of services by any provider who has been notified of the need for medical necessity review, due to billing practices or claims that are not consistent with other providers in terms of frequency or some other manner.

General Clinical Guideline

Clinical Appropriateness Framework

Critical to any finding of clinical appropriateness under the guidelines for a specific diagnostic or therapeutic intervention are the following elements:

  • Prior to any intervention, it is essential that the clinician confirm the diagnosis or establish its pretest likelihood based on a complete evaluation of the patient. This includes a history and physical examination and, where applicable, a review of relevant laboratory studies, diagnostic testing, and response to prior therapeutic intervention.
  • The anticipated benefit of the recommended intervention is likely to outweigh any potential harms, including from delay or decreased access to services that may result (net benefit).
  • Widely used treatment guidelines and/or current clinical literature and/or standards of medical practice should support that the recommended intervention offers the greatest net benefit among competing alternatives.
  • There exists a reasonable likelihood that the intervention will change management and/or lead to an improved outcome for the patient.

Providers may be required to submit clinical documentation in support of a request for services. Such documentation must a) accurately reflect the clinical situation at the time of the requested service, and b) sufficiently document the ordering provider’s clinical intent.

If these elements are not established with respect to a given request, the determination of appropriateness will most likely require a peer-to-peer conversation to understand the individual and unique facts that would justify a finding of clinical appropriateness. During the peer-to-peer conversation, factors such as patient acuity and setting of service may also be taken into account to the extent permitted by law.

Simultaneous Ordering of Multiple Diagnostic or Therapeutic Interventions

Requests for multiple diagnostic or therapeutic interventions at the same time will often require a peer-to-peer conversation to understand the individual circumstances that support the medical necessity of performing all interventions simultaneously. This is based on the fact that appropriateness of additional intervention is often dependent on the outcome of the initial intervention.

Additionally, either of the following may apply:

  • Current literature and/or standards of medical practice support that one of the requested diagnostic or therapeutic interventions is more appropriate in the clinical situation presented; or
  • One of the diagnostic or therapeutic interventions requested is more likely to improve patient outcomes based on current literature and/or standards of medical practice.

Repeat Diagnostic Intervention

In general, repeated testing of the same anatomic location for the same indication should be limited to evaluation following an intervention, or when there is a change in clinical status such that additional testing is required to determine next steps in management. At times, it may be necessary to repeat a test using different techniques or protocols to clarify a finding or result of the original study.

Repeated testing for the same indication using the same or similar technology may be subject to additional review or require peer-to-peer conversation in the following scenarios:

  • Repeated diagnostic testing at the same facility due to technical issues
  • Repeated diagnostic testing requested at a different facility due to provider preference or quality concerns
  • Repeated diagnostic testing of the same anatomic area based on persistent symptoms with no clinical change, treatment, or intervention since the previous study
  • Repeated diagnostic testing of the same anatomic area by different providers for the same member over a short period of time

Repeat Therapeutic Intervention

In general, repeated therapeutic intervention in the same anatomic area is considered appropriate when the prior intervention proved effective or beneficial and the expected duration of relief has lapsed. A repeat intervention requested prior to the expected duration of relief is not appropriate unless it can be confirmed that the prior intervention was never administered. Requests for on-going services may depend on completion of previously authorized services in situations where a patient’s response to authorized services is relevant to a determination of clinical appropriateness.

Prenatal Testing using Cell-free DNA

Description and Scope

Cell-free DNA (cfDNA) screening for aneuploidy, sometimes called noninvasive prenatal testing (NIPT) or noninvasive prenatal screening (NIPS), evaluates DNA from the placenta in the maternal circulation to screen for specific chromosomal abnormalities, known as aneuploidies, in the pregnancy.

These tests can identify pregnancies at increased risk for these conditions but cannot definitively diagnose, confirm, or exclude them. Screening tests that show increased risk should be confirmed by diagnostic testing prior to any intervention.

For testing associated with reproduction, see Carrier Screening in the Prenatal Setting guideline.

General Recommendations

Genetic counseling

The approach chosen for any prenatal screening technique should involve shared decision-making between the patient and the clinician. Counseling is encouraged prior to any prenatal screening that involves cell-free DNA and should include ALL of the following components:

  • Clearly defined differences between screening and diagnostic prenatal genetic testing
  • Risk assessment for and education about aneuploidies
  • Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition
  • Counseling for the psychological aspects of genetic testing

Note: Post-test counseling should be performed for any positive or non-reportable cfDNA screen result.

Rationale

As stated above, it should be stressed that this specific type of testing is a screening modality, as opposed to a diagnostic one. Additionally, the approach chosen for any prenatal screening technique should involve shared decision-making between the patient and the clinical team. Like any other genetic screening test, cell-free DNA testing is a process that involves risk that accompanies its potential benefits and, therefore, the clinical team and the patient should consider the balance of risks and potential benefits before testing is pursued through informed consent. Furthermore, the clinical utility of a genetic screening test must be considered along with its psychological and sociological implications.1 Counseling, either by a genetic counselor and/or team clinician, provides a patient-centered approach to the care of individuals who are undergoing a genetic screening test, such as prenatal testing.

It is also recognized that the accessibility to genetic counselors is limited by available resources as well as other social determinants of health. Therefore, as it relates to screening, the importance should be placed on counseling in a general sense, such as informed consent, as noted above.

As with any genetic test, whether for screening or diagnosis, genomic technologies generate large amounts of data, and this increases the potential for uncertainty in managing and adapting to this information. The clinical team is tasked with accurately interpreting and communicating information about test validity and the reliability of test results, as well as the probability for individual patient benefit.2 Uncovering incidental findings and being overwhelmed with information are important possible consequences to genetic testing, particularly among vulnerable patient subgroups.3 Counseling is an invaluable resource for patients undergoing genetic screening testing, but there are practical limitations because of the scarcity of resources relative to the current need, as noted above.

Clinical Indications

General Requirements

Prenatal testing using cfDNA should occur only once per fetus per pregnancy.

Condition-Specific Requirements

Viable singleton or twin pregnancy

Prenatal testing using cell-free DNA (cfDNA) is considered medically necessary as a screening test in viable singleton or twin pregnancy at 9 weeks gestation or later for ANY of the following chromosomal abnormalities:

  • Trisomy 13
  • Trisomy 18
  • Trisomy 21
  • Sex chromosome aneuploidies affecting the X or Y chromosome

AND/OR

  • Sex prediction for pregnancies at risk for an X-linked disorder
Not Medically Necessary:

The use of this testing for routine screening and evaluation of chromosomal abnormalities other than those listed is considered not medically necessary including, but not limited to, the following:

  • Fetal sex determination
  • Higher order multiple gestation pregnancies (≥ 3 fetuses)
  • Twin zygosity (i.e., differentiating between monozygotic and dizygotic twins)
  • When the current pregnancy is affected by a fetal demise, vanishing twin, or one or more abnormalities detected in the fetus(s)
  • Screening for single gene (monogenic) disorders
  • Aneuploidies of other autosomal chromosomes
  • Microdeletions or microduplications
  • Whole genome or exome screening
  • Fetal RhD status
  • Non-viable pregnancies
  • Testing associated with serum screening (either concurrent or follow up)
  • Testing in conjunction with other biomarkers

Note: Some of the tests listed above have a role in care under certain circumstances, but they should not be routinely offered.

Rationale

Chromosomal abnormalities (aneuploidy, translocations, duplication, or deletions) are present in approximately 1 in 150 live births, with 3% to 5% of pregnancies ultimately complicated by birth defects or genetic disorders.4 For various reasons, some patients choose to pursue screening for underlying genetic disorders with decisions about such testing and possible subsequent actions being driven heavily by patient values. Various screening techniques are available, and the field is rapidly evolving. Techniques in the first trimester include serum screening using markers (such as beta human chorionic gonadotropin, alpha-fetoprotein, inhibin A, and unconjugated estriol), and ultrasound testing to assess nuchal translucency. Integrated screening techniques produce a detection rate of about 96% with around 5% false positives.4

Over the past 10 years, the rapid advances in genomic medicine have brought new technology into use for prenatal screening. Non-invasive prenatal testing (NIPT) refers to sequence analysis of placental cell-free DNA (cfDNA) fragments that circulate in the blood of pregnant women, along with the translation of this method into screening for chromosome abnormalities. Approaches for NIPT include shotgun whole genome and targeted sequencing.5 The shotgun approach of whole genome sequencing generates short sequences from across the genome which are then aligned to a reference chromosome and counted. In contrast, targeted sequencing of the cfDNA is based on next-generation sequencing (NGS) and involves amplification of selected chromosomal loci on the chromosomes of interest.6 The challenge of picking the diagnostic “needle” becomes greater as the size of the “haystack” shifts from targeted testing to the whole genome, and the number of variants that must be filtered out in practice because they are unrelated to the patient’s phenotype is greater when more sensitive methodologies are used.7 Of note, while NIPT methods can detect chromosomal abnormalities in pregnancy after 10 weeks gestation, they do not assess the risk of fetal structural anomalies such as neural tube defects or ventral wall defects.6

NIPT was initially validated as a clinical prenatal screen for pregnancies at high risk for trisomy 21, and it has since been approved to determine fetal sex and screen for fetal aneuploidy, including trisomies 13 (Patau syndrome), 18 (Edward syndrome), and 21 (Down syndrome) in high-risk and average risk pregnancies.6 At any given maternal age, the rate of common trisomies is similar between singleton and twin pregnancies, and NIPT screening provides higher predictive values among twin pregnancies compared to traditional serum and nuchal translucency based techniques.8 A systematic evidence review evaluating NIPT for screening in a general risk population found that it is the most effective screening approach for trisomies 13, 18, and 21 in singleton and twin gestations with both high detection and low false-positive rates.9 Several professional society guidelines endorse genetic counseling prior to prenatal screening in order to explore the conditions being screened, the patient’s desire avidity for this information, and follow-up logistics and decision-making options. Definitive diagnosis of abnormalities detected on screening requires sampling of pregnancy tissue by chorionic villous sampling or amniocentesis for chromosomal array analysis.6

The position of the American College of Obstetrics and Gynecology (ACOG) and the Society of Maternal Fetal Medicine (SMFM) in 2020 is that “prenatal genetic screening (serum screening with or without nuchal translucency 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 maternal age or risk of chromosomal abnormality. After review and discussion, every patient has the right to pursue or decline prenatal genetic screening and diagnostic testing.”10 The American College of Medical Genetics and Genomics (ACMG) position has also been favorable towards offering women the option of cell-free DNA screening, ultimately recommending that patients receive accurate and balanced information to promote patient-centered, nondirective decision-making.11 The ACMG specifically recommends informing all pregnant women that cfDNA screening is the most sensitive screening option for common aneuploidies, does not recommend maternal age or risk of chromosomal abnormality as a basis to choose between aneuploidy testing approaches, and does not recommend having multiple screening methods performed simultaneously.12

References

1. Knob AL. Principles of genetic testing and genetic counseling for renal clinicians. Semin Nephrol. 2010;30(4):431-7.

2. Pollard S, Sun S, Regier DA. Balancing uncertainty with patient autonomy in precision medicine. Nat Rev Genet. 2019;20(5):251-2.

3. Borno HT, Rider JR, Gunn CM. The Ethics of Delivering Precision Medicine-Pretest Counseling and Somatic Genomic Testing. JAMA Oncol. 2020;6(6):815-6.

4. Carlson LM, Vora NL. Prenatal Diagnosis: Screening and Diagnostic Tools. Obstet Gynecol Clin North Am. 2017;44(2):245-56.

5. Bianchi DW, Chiu RWK. Sequencing of Circulating Cell-free DNA during Pregnancy. N Engl J Med. 2018;379(5):464-73.

6. Allyse MA, Wick MJ. Noninvasive Prenatal Genetic Screening Using Cell-free DNA. JAMA. 2018;320(6):591-2.

7. Liu P, Vossaert L. Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing. Prenat Diagn. 2022;42(6):686-96.

8. Palomaki GE, Chiu RWK, Pertile MD, et al. International Society for Prenatal Diagnosis Position Statement: cell free (cf)DNA screening for Down syndrome in multiple pregnancies. Prenat Diagn. 2021;41(10):1222-32.

9. Rose NC, Barrie ES, Malinowski J, et al. Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies. Genet Med. 2022;24(7):1379-91.

10. American College of Obstetricians and Gynecologists (ACOG). Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol. 2020;136(4):e48-e69.

11. 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. 2016;18(10):1056-65.

12. Gregg AR, Rajkovic A. Cell-Free DNA Screening During Pregnancy. JAMA. 2019;321(3):308-9.

Codes

The following code list is not meant to be all-inclusive. Authorization requirements will vary by health plan. Please consult the applicable health plan for guidance on specific procedure codes.

Specific CPT codes for services should be used when available. Nonspecific or not otherwise classified codes may be subject to additional documentation requirements and review.

CPT/HCPCS

CPT® (Current Procedural Terminology) is a registered trademark of the American Medical Association (AMA). CPT® five-digit codes, nomenclature and other data are copyright by the American Medical Association. All Rights Reserved. AMA does not directly or indirectly practice medicine or dispense medical services. AMA assumes no liability for the data contained herein or not contained herein.

May Be Medically Necessary When Criteria are Met

Code

May Be Medically Necessary When Criteria are Met

81420

Fetal chromosomal aneuploidy (eg, 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

81479

Unlisted molecular pathology procedure

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

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as cell-free fetal DNA-based prenatal testing involving multianalyte assays and an algorithmic analysis for fetal aneuploidy]

0327U

Fetal aneuploidy (trisomy 13, 18, and 21), DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score for each trisomy, includes sex reporting, if performed

Not Medically Necessary

Code

Not Medically Necessary

81422

Fetal chromosomal microdeletion(s) genomic sequence analysis (eg, DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA in maternal blood.

0060U

Twin zygosity, genomic targeted sequence analysis of chromosome 2, using circulating cell-free fetal DNA in maternal blood

0341U

Fetal aneuploidy DNA sequencing comparative analysis, fetal DNA from products of conception, reported as normal (euploidy), monosomy, trisomy, or partial deletion/duplication, mosaicism, and segmental aneuploid

ICD-10 Diagnosis

Refer to the ICD-10 CM manual

History

Status

Review Date

Effective Date

Action

Revised

07/18/2023

03/17/2024

Independent Multispecialty Physician Panel (IMPP) review. Clarified required components of genetic counseling. For viable singleton or twin pregnancy, clarified sex prediction for pregnancies at risk for an X-linked disorder. Updated references. Split codes into those considered medically necessary when criteria are met (MNWCM) and not MN. Added CPT 0341U (NMN). Added required language per new Medicare regulations.

Updated

n/a

10/01/2023

Added CPT code 81599.

Created

09/21/2022

02/12/2023

IMPP review. Original effective date.

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