UnitedHealthcare cfDNA Testing Coverage Update

Coverage Criteria

inv-01: RhD genotyping / alloimmunization — medical necessity

Covered when ALL of the following are met

RhD/alloimmunization indication: Individual is alloimmunized or at risk for alloimmunization due to maternal RhD status or presence of red cell antigen antibodies.

Paternal genotype: Paternal genotyping shows heterozygosity for RhD or paternal RhD status is unknown.

Invasive testing offered and declined: Indicated invasive diagnostic testing (e.g., amniocentesis, chorionic villus sampling) for fetal genotyping has been offered and declined.

inv-02: Unproven / Not medically necessary indications

Not medically necessary / unproven indications

Expanded/exome/genome-wide testing: Genome-wide or exome-wide screening and expanded cfDNA panels that include testing beyond trisomies 21, 18, 13, and sex chromosome aneuploidy are considered unproven and not medically necessary.

Microdeletions/CNVs and single-gene disorders: Screening for microdeletions/microduplications/CNVs or single-gene disorders is considered unproven and not medically necessary.

Fetal antigen other than RhD: Fetal antigen status testing other than RhD is considered unproven and not medically necessary.

Twin zygosity: Testing performed solely to determine twin zygosity is considered unproven and not medically necessary.

inv-03: General coverage summary — Coverage stance based on evidence presented in this section

Coverage stance based on evidence presented in this section:

General coverage rationale: cfDNA screening is supported for common trisomies and sex chromosome aneuploidies as the most accurate screening option, but evidence is insufficient to support routine screening for rare autosomal aneuploidies (RATs), genome-wide CNVs/microdeletions, and prenatal exome/genome sequencing due to low/variable positive predictive values and unclear clinical utility.

inv-04: RATs (rare autosomal trisomies) — RATs / Rare autosomal aneuploidies — coverage considerations

RATs / Rare autosomal aneuploidies — coverage considerations:

RAT findings: Reporting of rare autosomal trisomies (RATs) by cfDNA has low pooled positive predictive value and high heterogeneity; many positives reflect placental mosaicism rather than true fetal trisomy.

Clinical actions after RAT-positive cfDNA: Confirmatory invasive diagnostic testing is required to establish fetal status; consider increased prenatal monitoring when placental mosaicism is suspected due to associated adverse outcomes.

inv-05: CNVs and microdeletions — CNVs and microdeletions (including 22q11.2) — coverage considerations

CNVs and microdeletions (including 22q11.2) — coverage considerations:

CNV/microdeletion performance: Performance of cfDNA for CNVs and specific microdeletions is variable across studies; some syndromes (e.g., 22q11.2) and larger CNVs show moderate-to-high PPV in selected cohorts, but sensitivity, PPV, and generalizability are inconsistent and false positives occur.

Diagnostic confirmation: Positive cfDNA results for CNVs or microdeletions should be confirmed with invasive diagnostic testing such as chromosomal microarray (CMA) before making pregnancy management decisions.

inv-06: Comparison with diagnostic testing (CMA) — Relative value compared to diagnostic CMA

Relative value compared to diagnostic CMA:

Comparative utility: Genome-wide cfDNA screening identifies only a small fraction of clinically significant findings that would be detected by diagnostic CMA; CMA remains the more comprehensive diagnostic test.

inv-07: Professional society guidance — Professional society recommendations relevant to cfDNA screening

Professional society recommendations relevant to cfDNA screening:

ACMG guidance: ACMG recommends prenatal cfDNA screening over traditional methods for trisomies 13, 18, and 21 in singleton and twin gestations, suggests offering screening for 22q11.2 conditionally, and states insufficient evidence for routine screening for CNVs other than 22q11.2 or routine RAT screening.

ACOG/SMFM guidance: ACOG recommends discussing and offering prenatal genetic screening (including cfDNA) and diagnostic testing to all pregnant individuals, emphasizes that cfDNA is a screening (not diagnostic) test, and advises confirmatory diagnostic testing and counseling for screen-positive results; ACOG/SMFM do not recommend routine genome-wide CNV or microdeletion screening due to lack of clinical validation.

ISPD/others: ISPD and other societies note NIPT is the most accurate screening test for common autosomal aneuploidies but recommend established pathways for no-call results and caution that data are insufficient for routine use of NIPT for RATs and routine CNV/microdeletion screening.

inv-08: Evidence summaries by indication — Evidence-based performance summaries and coverage-relevant findings by indication (selected examples)

Evidence-based performance summaries and coverage-relevant findings by indication (selected examples):

22q11.2 microdeletion screening: SNP-based cfDNA screening for 22q11.2 reports sensitivity in some studies between ~75% and 90% with very high specificity (~99%+); PPV is variable and limited by low prevalence but can improve with algorithm updates; confirmatory diagnostic testing is recommended for positive results.

CNV detection: Detection of CNVs by expanded or genome-wide cfDNA shows variable sensitivity and PPV depending on CNV size, testing platform, and population; performance in selected cohorts with ultrasound anomalies is higher than in average-risk populations.

Fetal antigen genotyping: NGS-based cfDNA assays for fetal antigen genotyping (including RhD and select non-Rh antigens) have reported high analytic and clinical concordance in some studies, showing potential utility in alloimmunized pregnancies, but further outcome-focused validation is needed.

inv-09: General coverage criteria and management — Covered when ALL of the following aligned with professional guidance

Covered when ALL of the following aligned with professional guidance:

Screening offered to all: cfDNA may be offered and discussed as a prenatal screening option to all pregnant individuals regardless of age or baseline risk; it is a screening test and not diagnostic, and positive results should be confirmed with diagnostic testing.

Follow-up to positive serum screen: cfDNA can be used as an option following a screen-positive serum analyte when patients wish to avoid invasive diagnostic testing, with counseling that this may delay definitive diagnosis.

No-call management: When cfDNA results are not reported or uninterpretable (no-call), patients should receive genetic counseling, comprehensive ultrasound evaluation, and be offered diagnostic testing; repeat NIPT may be considered per protocol.

Multiple gestation considerations:

inv-10: Applications not recommended — Not recommended / limited clinical utility

Not recommended / limited clinical utility:

Single-gene cfDNA screening: ACOG does not recommend single-gene cfDNA screening for general population use due to insufficient evidence of clinical validity and predictive values.

Microdeletion and genome-wide CNV screening: ACOG/SMFM state that microdeletion and genome-wide CNV cfDNA screening have not been clinically validated and are not recommended for routine use.

inv-11: Fetal blood group genotyping — Specific application supported with evidence and cost considerations

Specific application supported with evidence and cost considerations:

Fetal RhD genotyping for antenatal prophylaxis: High-throughput cfDNA testing for fetal RhD genotype can guide antenatal anti-D prophylaxis decisions and reduce unnecessary use of blood products when cost-effectiveness thresholds are met.

inv-12: Fetal genotype determination in alloimmunized or at-risk pregnancies

Covered when ALL of the following are met for fetal genotype determination in alloimmunized or at-risk pregnancies

Primary coverage criteria: Individual undergoing testing is alloimmunized or at risk for alloimmunization due to maternal RhD status or presence of red cell antigen antibodies.

Paternal genotype requirement: Paternal genotyping shows heterozygosity for RhD or paternal RhD status is unknown.

Invasive testing offered and declined: Indicated invasive diagnostic testing (e.g., amniocentesis, CVS) for fetal genotyping has been offered and declined and this is documented.

Genome-wide or exome-wide screening and expanded cfDNA panels that include targets beyond common aneuploidies (trisomies 21, 18, 13) and sex chromosome aneuploidy are considered unproven and not medically necessary. The policy specifically lists genome-wide/exome-wide approaches and expanded panels as excluded from routine coverage, and it notes that current evidence is insufficient to establish clinical utility for broad CNV/microdeletion screening or prenatal exome/genome sequencing. Confirmatory diagnostic testing (e.g., amniocentesis with chromosomal microarray) is recommended when such expanded cfDNA results are reported due to high false-positive rates in the published literature.

Routine use of cfDNA for prenatal exome/genome sequencing, for CNV screening in twin pregnancies, or for broadly screening rare aneuploidies/microdeletions is not supported by current evidence and therefore is excluded from routine coverage. The policy highlights lack of peer-reviewed clinical utility data for these approaches and identifies particularly limited evidence for twin gestations, where no clinical-utility studies were identified.

The American College of Medical Genetics and Genomics (ACMG) states there is insufficient evidence to recommend routine prenatal cfDNA screening for copy number variants (CNVs) other than the 22q11.2 deletion and insufficient evidence to recommend routine screening for rare autosomal trisomies (RATs). ACMG’s guidance therefore does not support routine genome-wide CNV screening by cfDNA outside of targeted or research contexts.

ACOG/SMFM publications note that genome-wide cfDNA screening intended to detect large deletions and duplications and routine microdeletion screening have not been clinically validated and are not recommended. The policy echoes this position, indicating that routine cfDNA microdeletion screening and genome-wide CNV approaches lack sufficient accuracy and validation to support routine clinical use.

UnitedHealthcare considers cfDNA testing using maternal plasma to determine fetal genotype proven and medically necessary only for specific alloimmunization indications; for other expanded indications, cfDNA is regarded as unproven and not medically necessary. The policy revision clarifies that testing beyond standard aneuploidy screening—including expanded panels, genome- or exome-wide analyses, microdeletion/CNV screens, and most single-gene screenings—are not supported for routine coverage.

Cell-free fetal DNA testing using maternal plasma is considered unproven and not medically necessary for indications beyond screening for trisomies 21, 18, 13, and sex chromosome aneuploidy. Examples of excluded routine uses include single-gene population screening, fetal antigen testing other than RhD, and testing solely to determine twin zygosity.

Additional indications listed as unproven or not medically necessary include genome-wide/exome-wide screening, expanded cfDNA panels beyond common trisomies and sex chromosome aneuploidy, microdeletions/microduplications/CNV screening, and single-gene disorder screening. The Instructions for Use section explicitly enumerates these as examples of applications that lack sufficient evidence to support routine coverage.

Use of cfDNA testing to evaluate single-gene disorders remains in early development with limited evidence from small studies. ACOG has stated there is insufficient evidence to support single-gene cfDNA screening for general-population use, and the policy lists single-gene NIPT approaches among indications considered unproven or not medically necessary pending further validation.

Routine single-gene cfDNA screening and unvalidated genome-wide CNV/microdeletion cfDNA screening are not supported by sufficient evidence for general population use. The policy therefore does not endorse these approaches for routine coverage and identifies them among not medically necessary indications.

Cell-Free Fetal DNA expanded panel testing—that is, panels that include targets beyond trisomies 21, 18, 13, and sex chromosome aneuploidy—is specifically listed as limited/not covered. This revision clarifies that expanded panel testing and other previously listed expanded uses are considered unproven and not medically necessary for routine screening.

Covered Indications

inv-59: Screening for trisomies 21, 18, 13, and sex chromosome aneuploidies as standard cfDNA/NIPT screening (screening only; positives require confirmatory invasive testing)

Standard aneuploidy screening: Screening for trisomies 21, 18, 13, and sex chromosome aneuploidies using cfDNA is offered as a screening test; positive results require confirmatory invasive diagnostic testing (CVS or amniocentesis).

inv-60: Screening for common trisomies (13, 18, 21) and sex chromosome aneuploidies — supported as effective screening tests; expanded indications require case-by-case consideration

Common trisomies and SCA: Screening for common trisomies (13, 18, 21) and sex chromosome aneuploidies is supported as an effective screening test; expanded indications should be considered case-by-case given evidence limitations.

inv-61: Screening for common fetal trisomies (13, 18, 21) and SCA in singleton and twin gestations — ACMG/ACOG recommendations

Coding and Billing

Applicable CPT/HCPCS/PLA Codesmixed

0060U	Twin zygosity, genomic targeted sequence analysis of chromosome 2, using circulating cell-free fetal DNA in maternal blood.
0488U	Obstetrics (fetal antigen noninvasive prenatal test), cell-free DNA sequence analysis for detection of fetal presence or absence of 1 or more of the Rh, C, c, D, E, Duffy (Fya), or Kell (K) antigen in alloimmunized pregnancies, reported as selected antigen(s) detected or not detected.
0489U	Obstetrics (single-gene noninvasive prenatal test), cell-free DNA sequence analysis of 1 or more targets (e.g., CFTR, SMN1, HBB, HBA1, HBA2) to identify paternally inherited pathogenic variants, and relative mutation-dosage analysis based on molecular counts to determine fetal inheritance of maternal mutation, algorithm reported as a fetal risk score for the condition (e.g., cystic fibrosis, spinal muscular atrophy, beta hemoglobinopathies [including sickle cell disease], alpha thalassemia).
0494U	Red blood cell antigen (fetal RhD gene analysis), next-generation sequencing of circulating cell-free DNA (cfDNA) of blood in pregnant individuals known to be RhD negative, reported as positive or negative.
0536U	Red blood cell antigen (fetal RhD), PCR analysis of exon 4 of RHD gene and housekeeping control gene GAPDH from whole blood in pregnant individuals at 10+ weeks gestation known to be RhD negative, reported as fetal RhD status.
81422	Fetal chromosomal microdeletion(s) genomic sequence analysis (e.g., DiGeorge syndrome, Cri-du- chat syndrome), circulating cell-free fetal DNA in maternal blood.
81479	Unlisted molecular pathology procedure

Removed CPT CodesCPT

0327U	removed from Applicable Codes
81420	removed from Applicable Codes
81507	removed from Applicable Codes

Removed ICD-10 Codes (partial list shown)ICD-10

O09.00	removed from policy ICD-10 list
Z34.00	removed from policy ICD-10 list

Earliest gestational age for testing

Earliest commonly available gestational age10+ weeks gestation (tests often available at 10 weeks); some studies report performance beginning at 9 weeks

Earliest reported performance in validation study9 weeks gestation (NGS-based RhD assay reporting sensitivity/NPV beginning at 9 weeks)

Policy summary statementcfDNA screening is offered as early as 10 weeks gestation; results are contingent on assay quality metrics and fetal fraction

nuchal translucency (NT)

NT thresholdNuchal translucency (NT) ≥ 3.5 mm

Recommended action

Provider Actions and Operational Notes

Billing Rule

Code Listing and Prior Authorization Implication

The following procedure and diagnosis codes are provided for reference only. Inclusion does not guarantee coverage; benefit, contractual, and state/federal requirements apply. Prior authorization expectations vary by benefit and contract — verify benefit-specific prior authorization before ordering.

0060U — Twin zygosity, genomic targeted sequence analysis of chromosome 2, using circulating cfDNA
0488U — Obstetrics fetal antigen NIPT for Rh and other red cell antigens in alloimmunized pregnancies
0489U — Single-gene NIPT for paternally inherited pathogenic variants (e.g., CFTR, SMN1, HBB)
0494U — cfDNA NGS fetal RhD gene analysis (reported positive/negative)
0536U — PCR analysis of exon 4 of RHD gene for fetal RhD status
81422 — Fetal chromosomal microdeletion(s) genomic sequence analysis (e.g., DiGeorge)
81479 — Unlisted molecular pathology procedure

Not Covered / Unproven Uses

The policy’s not-covered list includes genome-wide or exome-wide screening, expanded cfDNA panels beyond trisomies 21/18/13 and sex chromosome aneuploidy, microdeletions/CNV screening, and single-gene NIPD where evidence is insufficient. Expanded panel testing beyond common trisomies and SCA is explicitly added to the revised not medically necessary items.

Routine cfDNA use for prenatal exome/genome sequencing and broad microdeletion/CNV screening without a clear, evidence-based indication is not supported by current data and is included among indications not covered by this policy. The policy notes the absence of peer-reviewed clinical-utility studies for these applications.

Routine screening for CNVs other than 22q11.2 deletions and routine screening for rare autosomal trisomies (RATs) are not supported by sufficient evidence; ACMG and ACOG/SMFM guidance cite lack of validation and low/variable positive predictive values for these uses, and the policy therefore excludes routine coverage.

Additional not-covered items summarize that cfDNA applications beyond standard trisomy and sex chromosome screening are considered unproven. The policy revision consolidates these expanded uses into the not medically necessary category to align coverage with current evidence.

Expanded panel testing beyond trisomies 21, 18, 13, and sex chromosome aneuploidy is specifically listed among revised not medically necessary items. The policy history documents this change and the removal or replacement of other previously listed expanded uses to reflect current evidence-based exclusions.

Eligibility Requirements

No top-level eligibility criteria are specified in this excerpt beyond the covered indication requirements described elsewhere in the policy.

Eligibility for RhD/fetal genotype testing in alloimmunized or at-risk pregnancies requires documentation that the pregnant individual is alloimmunized or at risk, and that paternal genotyping shows heterozygosity for RhD or paternal RhD status is unknown; the policy revision also requires that indicated invasive diagnostic testing be offered and declined.

Family history criteria are not detailed for most cfDNA indications in the provided text. For single-gene NIPD (e.g., RHDO) and targeted approaches, prior molecular diagnosis in the family and reference samples may be required for assay design and interpretation, but these requirements are not enumerated as general eligibility criteria for screening cfDNA tests.

For single-gene NIPD approaches, prior molecular diagnosis in an affected family member and the availability of reference samples for phasing may be necessary to design and validate the assay; the policy notes these are procedure-specific requirements rather than broad eligibility criteria.

No additional top-level eligibility nodes are specified in this excerpt.

The policy indicates documentation should support alloimmunization status or risk, paternal genotyping results, and that invasive diagnostic testing was offered and declined when fetal genotype determination is being requested for alloimmunized or at-risk pregnancies; for RHDO-based or single-gene NIPD, prior molecular diagnosis and reference samples may be required for testing to proceed.

Background

Cell-free fetal DNA (cfDNA) circulating in maternal blood can be analyzed noninvasively starting in the first trimester (commonly available at 10+ weeks gestation) to screen for common fetal aneuploidies. cfDNA is a screening test, not diagnostic; screen-positive or inconclusive results should prompt genetic counseling and offer of confirmatory invasive diagnostic testing (e.g., CVS or amniocentesis with chromosomal microarray).

Definitions

Aneuploidy definition

DefinitionAneuploidy: an abnormal number of chromosomes (extra or missing), including trisomy and monosomy

Common examplesExamples include Down syndrome (trisomy 21), Patau syndrome (trisomy 13), and Edwards syndrome (trisomy 18)

Scope noteAneuploidy can affect autosomes and sex chromosomes; impacts depend on chromosome involved

Cell-Free Fetal DNA definition

DefinitionCell-Free Fetal DNA (cffDNA or cfDNA): small fragments of fetal DNA from the placenta circulating in maternal blood

UseAnalyzed via noninvasive prenatal screening to assess risk for fetal aneuploidies and other genetic anomalies

Quick Provider Guidance

Documentation Required

Provide genetic counseling before and after testing

Genetic counseling is strongly recommended prior to fetal screening or prenatal diagnosis to explain advantages, limitations, screening vs diagnostic distinctions, and potential follow‑up steps.

Policy counseling requirements emphasize pre‑ and post‑test genetic counseling, especially for expanded testing and positive or no‑call results.
ACOG and ISPD recommend counseling as part of standard pretest information for cfDNA screening.

Note

Prior Authorization

Order cfDNA in accordance with guidelines and ensure counseling/follow‑up

Revision History

2026-04-01revisionLatest

Template update and administrative edits including removal of content/language pertaining to the state of Louisiana.

2025-08-01material_revision

Coverage rationale updated: added criteria that cfDNA testing of maternal plasma to determine fetal genotype is proven and medically necessary for alloimmunized or at-risk pregnancies when paternal genotyping is heterozygous or unknown and indicated invasive diagnostic testing has been offered and declined; removed prior language stating DNA-based NIPT are proven and medically necessary for listed high-risk screening circumstances.

This policy was revised to add coverage language for cfDNA RhD genotyping in alloimmunized pregnancies with specific documentation requirements and to mark expanded panel testing beyond trisomies and sex chromosome aneuploidy as not medically necessary.

OpenPayer

Cell‑Free Fetal DNA Testing