Prenatal Cell-free DNA Testing and Maternal Serum Screening (MSS)
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Governance of coverage and medical necessity criteria for prenatal cell-free DNA testing (NIPT) and MSS including aneuploidies, microdeletions, single-gene disorders, fetal RhD genotyping; applies to pregnant members and ordering providers.
Policy name changed from 'Non-Invasive Prenatal Screening (NIPS)' to 'Prenatal Cell-free DNA Testing' / 'Prenatal Screening' and criteria sets were updated to reflect ACMG guidance.
A new criteria section created for Prenatal Cell-free DNA Testing for Fetal RhD Genotyping.
Statements that tests for microdeletions via cfDNA (including 22q11.2) currently have insufficient evidence to improve health outcomes versus standard of care.
Coverage Criteria for Prenatal Screening
Prenatal Cell-free DNA Testing for Chromosome 13, 18, 21, X and Y Aneuploidies
Covered when ALL of the following are met:
Applies to cfDNA screening for chromosomes 13, 18, 21, X, and Y.
Prenatal Cell-free DNA Testing for Microdeletions
Testing for microdeletions (including 22q11.2) via cfDNA has low positive predictive value and insufficient evidence of improved clinical outcomes compared to standard of care.
Prenatal Cell-free DNA Testing for Single-gene Disorders
ACOG practice advisory states insufficient evidence regarding accuracy for single-gene conditions (examples include skeletal dysplasias, sickle cell disease, cystic fibrosis).
Prenatal Cell-free DNA Testing for Fetal RhD Genotyping
Covered when ALL of the following are met:
Qualifying conditions include practice settings experiencing RhIG shortages or documented unknown/heterozygous paternal RhD genotype; cfDNA RhD testing may also be considered in alloimmunized pregnancies as described in rationale.
Maternal Serum Screening (MSS)
Covered when ANY ONE of the following is used (one time per pregnancy):
Only one MSS approach should be used one time per pregnancy.
Prenatal cfDNA coverage groups
Coverage stance summarized by indication:
See full policy for timing, singleton vs multiple gestation specifics and counseling requirements.
Likely considered not supported/medically necessary absent strong justification.
Coverage restricted unless future evidence/guidance changes.
Alternate criteria permit coverage in these specific scenarios; refer to full policy for details.
cfDNA testing is not supported for indications beyond the policy-defined scope for common aneuploidies. Specifically, this policy does not support cfDNA for: aneuploidies other than chromosomes 13, 18, 21, X, and Y; pregnancies with triplets or higher-order multiples; use performed simultaneously with maternal serum screening (MSS); use in a singleton pregnancy with a known vanishing twin; or testing performed solely for fetal sex determination. Providers should confirm that the indication matches the aneuploidy coverage criteria before ordering to avoid denials.
Prenatal cfDNA screening for microdeletions is effectively excluded from standard coverage under this policy. The document states that current evidence does not support prenatal cfDNA testing for microdeletions for all indications and notes concerns about validation, low positive predictive values, and higher false positive rates when attempting microdeletion analysis via cfDNA.
The policy explicitly finds insufficient evidence to support routine prenatal cfDNA screening for microdeletions and for screening of mutations associated with single-gene disorders. Professional society guidance cited in the policy (ACOG/SMFM and ACOG practice advisories) emphasizes that these applications lack clinical validation and that evidence regarding test accuracy is insufficient for routine use.
Available validation studies and society guidance show that cfDNA microdeletion screening has a low positive predictive value (PPV) and higher false positive rates compared with common trisomy screening. The policy notes these performance limitations are largely attributable to the low population prevalence of individual targeted microdeletions and that current peer-reviewed evidence does not demonstrate improved health outcomes versus standard care.
Covered Indications and Situations
inv-30: Screening for fetal trisomies 13, 18, 21 and sex chromosome aneuploidies (X,Y); fetal RhD genotyping when criteria met; maternal serum screening (one of listed approaches).
Screening for fetal trisomies 13, 18, 21 and sex chromosome aneuploidies (X,Y); fetal RhD genotyping when criteria met; maternal serum screening (one of listed approaches).
Providers should document counseling and adhere to prior authorization requirements where applicable.
inv-31: Fetal RhD genotyping in settings such as RhIG shortages or alloimmunized pregnancies — ACOG and study concordance noted
Context and rationale supporting limited use of cfDNA RhD genotyping in specific settings:
This supports coverage in specified scenarios (e.g., RhIG shortages, heterozygous/unknown paternal RhD, or alloimmunized pregnancies).
inv-32: Screening for common aneuploidies (chromosomes 13,18,21,X,Y) — policy updated to include X and Y and twin zygosity where applicable
Policy update summary — scope of covered aneuploidies and twin zygosity:
See policy definitions and coding tables for examples of allowable testing and timing specifics.
Not Covered Services
Not covered under routine policy: prenatal cfDNA testing for microdeletions (including 22q11.2), cfDNA screening for single-gene disorders, testing for aneuploidies beyond chromosomes 13, 18, 21, X, and Y, testing in higher-order multiples (triplets or more), and testing in the context of a vanishing twin or when used simultaneously with MSS. These indications are identified as unsupported due to insufficient evidence of clinical validity or utility and are therefore generally not considered medically necessary.
Prenatal cfDNA testing for microdeletions (for example, 22q11.2) and for single-gene disorders is not supported by current evidence and is effectively excluded from coverage as standard practice. The policy references ACOG/SMFM and ACOG advisories noting lack of clinical validation and insufficient accuracy data for these applications.
Example Billing Codes and Coding Notes
| 81420 | Prenatal cfDNA testing for common aneuploidies (example listed) |
| 81507 | Harmony Prenatal Test (example listed) |
| 0060U | Panorama twin zygosity testing (example listed) |
| 0327U | Vasistera (example listed) |
| O09 | ICD-10 pregnancy codes referenced |
| O28 | ICD-10 pregnancy codes referenced |
| O30 | ICD-10 multiple gestation codes referenced |
| O35 | ICD-10 fetal evaluation/observation codes referenced |
| Q90-Q99 | ICD-10 congenital chromosomal anomalies range referenced |
| Z34 | ICD-10 routine prenatal care |
| 81422 | Prenatal cfDNA testing for microdeletions (example billing code) |
| 81508 | MSS - example CPT for maternal serum screening |
| 81509 | MSS - example CPT for maternal serum screening |
| 81510 | MSS - example CPT for maternal serum screening |
| 81511 | MSS - example CPT for maternal serum screening |
| 81512 | MSS - example CPT for maternal serum screening |
| 81302 | CPT for single-gene cfDNA testing - example listed |
| 81404 | CPT for single-gene cfDNA testing - example listed |
| 81405 | CPT for single-gene cfDNA testing - example listed |
| 81406 | CPT for single-gene cfDNA testing - example listed |
Provider Actions, Documentation, and Authorization
Obtain prior authorization for listed cfDNA/MSS test codes
Providers should follow the payer's prior authorization process for the specific CPT and PLA codes listed for prenatal cfDNA and MSS testing (examples include 81420, 81507, 0060U, 0327U, 81422, 81302, 81404, 81405, 81442, 0489U, 0488U, 0494U and MSS CPTs 81508–81512). Prior authorization requirements apply to tests referenced in the coding tables and example tests.
Use updated 'Prenatal Cell-free DNA Testing' titles and revised code lists when requesting prior authorization
Policy titles and coding tables were updated to use the term 'Prenatal Cell-free DNA Testing' and the coding examples were revised (e.g., 81405 called out for single-gene disorders); prior authorization requirements follow these updated titles and coding lists.
- Updated policy terminology from NIPS to 'Prenatal Cell-free DNA Testing'.
- Coding examples revised—81405 referenced for single-gene cfDNA testing; coding table updates affect prior authorization submissions.
Limit MSS to one approach per pregnancy and document the chosen approach
Maternal serum screening (MSS) is limited to a single approach once per pregnancy; document which MSS approach was used because coverage is for no more than one of the listed MSS options one time per pregnancy.
- Only one MSS approach per pregnancy is considered medically necessary (first trimester, second trimester, integrated/stepwise/contingent, or penta).
- Document which MSS approach was performed to support coverage.
Step therapy: not applicable
No explicit step therapy is specified in this policy; there are no sequential therapy requirements stated for cfDNA or MSS within this document segment.
Document pre- and post-test genetic counseling including false-positive risk
Document that pre-test counseling discussed the potential for false-positive results, plans for returning results, and that pre-test and post-test genetic counseling (or referral) will be provided.
- Counsel about risk of false-positive results before testing.
- Document that pre-test and post-test genetic counseling facilitating informed decision-making and results return plans were provided or that referral to a genetics professional was arranged.
Document counseling on screening vs diagnostic options and avoid simultaneous screening approaches
Document counseling about available screening and diagnostic options (e.g., MSS, cfDNA, CVS, amniocentesis) and avoid performing multiple independent screening approaches in the same pregnancy because doing so increases false positives.
- Record discussion of screening versus diagnostic options and the patient's informed choice.
- Do not perform independent multiple screening approaches (e.g., MSS plus cfDNA) without documentation explaining rationale.
Avoid ordering tests for unsupported indications (denial risk)
Tests ordered for indications not supported by this policy—such as cfDNA for microdeletions (including 22q11.2), single-gene disorders for routine screening, higher‑order multiples (triplets+), simultaneous cfDNA with MSS, vanishing twin cases, or testing solely for fetal sex—may be denied as not medically necessary.
- cfDNA for microdeletions and single-gene disorders is considered unsupported and may be denied.
- Requests for cfDNA in triplets or higher, vanishing twin, simultaneous cfDNA+MSS, or for fetal sex determination only are not supported and may be denied.
Microdeletion cfDNA screening likely not covered—high false positive risk
Microdeletion cfDNA screening (including 22q11.2) is unlikely to be covered because studies show low positive predictive values and higher false-positive rates; orders for these tests may be denied absent strong justification.
- Microdeletion cfDNA testing has low PPV and higher false positives due to low prevalence.
- Coverage is not supported by current evidence and may be denied.
Provide and document pre- and post-test genetic counseling, including incidental findings and return-of-results plan
Pre-test and post-test genetic counseling is strongly advised; document that counseling was provided, that incidental/secondary finding risks were discussed, and include a plan for returning results to facilitate informed decision-making.
- Discuss and document possibility of secondary or incidental findings and how results will be returned.
- Refer to a trained genetics professional for increased‑risk or positive screening results.
Ensure and document pre-test counseling; refer positives to genetics specialists
Ensure pre-test counseling is performed and document it; if cfDNA screening returns an increased risk or positive result, refer the patient to a genetics professional for further evaluation and management.
- Ordering providers must ensure and document that pre-test counseling occurred.
- Refer to trained genetics professionals when increased risk or positive results are reported.
No explicit ordering restrictions—ordering clinician must ensure counseling and documentation
The policy does not impose explicit restrictions on who may order prenatal cfDNA or MSS tests in this segment; standard practice is that ordering clinicians ensure counseling and documentation are completed.
- No specific provider-type ordering limitations are stated here.
- Ordering clinicians remain responsible for counseling and documentation prior to ordering.
Eligibility Requirements
Eligibility criteria for covered cfDNA indications are specified elsewhere in the policy; this section includes no additional top-level eligibility nodes.
This policy segment does not establish any specific family history requirements for coverage decisions. Providers should document counseling and shared decision-making as recommended, but no family history thresholds are specified here.
No additional top-level eligibility nodes are specified in this portion of the policy; refer to the full coverage criteria for detailed inclusion conditions for aneuploidy screening and RhD genotyping.
Some aneuploidy coverage criteria explicitly require that the member has not previously had cfDNA screening in the current pregnancy; prior cfDNA in the same pregnancy may make repeat cfDNA screening ineligible under the policy.
Background
Cell-free DNA (cfDNA) testing is a screening method that analyzes fetal-derived fragments of DNA in maternal blood to assess risk for specific fetal genetic abnormalities. It is generally more sensitive and specific than traditional maternal serum screening for common aneuploidies but remains a screening—not diagnostic—test with potential false positives and false negatives. Professional guidance recommends pre-test and post-test genetic counseling to explain limitations and options for diagnostic confirmation when screening indicates increased risk.
Definitions
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