CurrentCapital BluecrossPolicy MP 2.278

Invasive Prenatal (Fetal) Diagnostic Testing

Capital Blue Cross medical policy MP 2.278 governs coverage and clinical criteria for invasive prenatal diagnostic testing (e.g., CMA, single-gene molecular testing, karyotype alternatives, NGS/WES) performed on fetal tissue obtained by amniocentesis, CVS, or other invasive procedures. This part (1 of 2) outlines covered modalities, investigational modalities, clinical indications/criteria, background, and coding guidance for the listed procedures.

Policy Summary

PayerCapital Bluecross

PolicyInvasive Prenatal (Fetal) Diagnostic Testing

Policy CodePolicy MP 2.278

Change TypeMultiple administrative and minor clinical revisions (see history)

Effective Date12/1/2025

Next Review Date

Key ActionEnsure invasive prenatal testing is performed only for appropriate indications and that informed pretest and posttest genetic counseling by a genetics-experienced clinician has been provided and documented.

SourceLink

POLICY UPDATE CHANGES

12/02/2021 Administrative Update added new code 81349 effective 01/01/2022.

07/27/2022 Administrative Update added 98 new ICD-10 codes and deleted 6 ICD-10 codes; added procedure codes 0335U & 0336U effective 10/01/2022.

10/24/2022 Minor Review designated low-pass sequencing as Medically Necessary and whole exome sequencing as Non-Medically Necessary; codes 0335U and 0336U classified as NMN.

06/12/2024 Administrative Update added 0469U as NMN effective 07/01/2024.

11/07/2024 Minor Review updated prenatal diagnostic whole exome sequencing to Investigational (INV) from NMN and updated codes 0335U, 0336U, and 0469U accordingly.

06/10/2025 Administrative Update added 0567U as NMN effective 07/01/2025.

06/12/2025 Administrative Update removed Benefit Variations Section and updated Disclaimer.

08/14/2025 Consensus Review noted: No changes to policy statement.

CMA MNCMA listed as medically necessary alternative to karyotype

INVWES/NGS listed as investigational for routine prenatal diagnostic use

May be MNLow-pass genome sequencing may be medically necessary as alternative to CMA

~100ICD-10 codes listed

4Procedure codes with classification changes

1Added molecular/genomic code 81349

Coverage Summary

This policy (MP 2.278) addresses invasive prenatal (fetal) diagnostic testing performed on fetal tissue obtained by procedures such as amniocentesis and chorionic villus sampling (CVS), and covers chromosomal microarray (CMA), molecular single-gene testing, low-pass genome sequencing, karyotype alternatives, and next-generation sequencing (NGS) approaches including whole exome/genome sequencing. The primary coverage stance is: CMA (chromosomal microarray) is medically necessary (MN) as an alternative to karyotyping; low-pass genome sequencing may be considered medically necessary as an alternative to CMA; and prenatal whole exome/NGS sequencing in the invasive prenatal diagnostic setting is considered investigational (not established for routine coverage).

Key policy highlights and thresholds

CMA stanceCMA considered medically necessary as an alternative to karyotyping; recommended for fetuses with major structural abnormalities

WES/NGS stanceWhole exome sequencing and other NGS approaches are considered investigational for routine prenatal diagnostic use due to limited evidence and high rates of VUS/false positives/negatives

Low-pass genome sequencing stanceLow-pass genome sequencing may be considered medically necessary as an alternative to CMA (classified MN on 10/24/2022)

ICD-10 countApproximately 100 ICD-10 diagnosis codes listed as examples for maternal care for suspected fetal abnormalities

Procedure codes with classification changesFour procedure/PLA/HCPCS codes have had coverage classification changes (0335U, 0336U, 0469U, 0567U)

Added code 81349Code 81349 was added to the coding list (Administrative Update 12/02/2021; effective 01/01/2022)

Laboratory CNV size cutoff thresholdLabs may establish size cutoffs for potentially pathogenic CNVs; typical range ~300 kb to 1 Mb

Medical Necessity Criteria

Chromosomal microarray (CMA) Testing

CMA testing may be considered medically necessary in patients undergoing invasive diagnostic prenatal testing, as an alternative to karyotyping. Low-pass genome sequencing may be considered medically necessary as an alternative to CMA.

ALL of the following

Patient is undergoing invasive diagnostic prenatal (fetal) testing (e.g., amniocentesis, CVS, cordocentesis)
CMA is used as an alternative to karyotyping or when recommended by clinical guidelines (e.g., fetus with one or more major structural abnormalities identified on ultrasound)

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Coding

Procedure codes - Investigational (Not covered) for NGS in invasive prenatal testingCPT|HCPCSNot Covered

81470	Next-generation sequencing (when used in setting of invasive prenatal testing) - Investigational
0335U	Investigational procedure code (listed as investigational for invasive prenatal NGS)
0336U	Investigational procedure code (listed as investigational for invasive prenatal NGS)
0469U	Investigational procedure code (listed as investigational for invasive prenatal NGS)

Procedure codes - Investigational (Not covered) for NGS in invasive prenatal testingCPT|HCPCSNot Covered

81470	Next-generation sequencing (when used in setting of invasive prenatal testing) - Investigational
0335U	Investigational procedure code (listed as investigational for invasive prenatal NGS)
0336U	Investigational procedure code (listed as investigational for invasive prenatal NGS)
0469U	Investigational procedure code (listed as investigational for invasive prenatal NGS)

Procedure codes - Covered when medically necessaryCPT|HCPCSCovered

81228	CMA / genomic microarray testing (covered when medically necessary)
81229	CMA / genomic microarray testing (covered when medically necessary)
81349	Molecular cytogenetics or related procedure (covered when medically necessary)
81405	Targeted gene sequencing or panel (covered when medically necessary)
0567U	Listed as covered when medically necessary

Procedure codes - Covered when medically necessaryCPT|HCPCSCovered

81228	CMA / genomic microarray testing (covered when medically necessary)
81229	CMA / genomic microarray testing (covered when medically necessary)
81349	Molecular cytogenetics or related procedure (covered when medically necessary)
81405	Targeted gene sequencing or panel (covered when medically necessary)
0567U	Listed as covered when medically necessary

ICD-10 Diagnosis codes - Examples listed as covered when medically necessaryICD-10Covered

O09.891	Supervision of other high-risk pregnancies, first trimester
O09.892	Supervision of other high-risk pregnancies, second trimester
O09.893	Supervision of other high-risk pregnancies, third trimester
O28.5	Abnormal chromosomal and genetic finding on antenatal screening of mother
O35.02X0	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, not applicable or unspecified
O35.02X1	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 1
O35.02X2	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 2
O35.02X3	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 3
O35.02X4	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 4
O35.02X5	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 5

1–10 of 25

1/3

ICD-10 Diagnosis codes - Examples listed as covered when medically necessaryICD-10Covered

O09.891	Supervision of other high-risk pregnancies, first trimester
O09.892	Supervision of other high-risk pregnancies, second trimester
O09.893	Supervision of other high-risk pregnancies, third trimester
O28.5	Abnormal chromosomal and genetic finding on antenatal screening of mother
O35.02X0	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, not applicable or unspecified
O35.02X1	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 1
O35.02X2	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 2
O35.02X3	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 3
O35.02X4	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 4
O35.02X5	Maternal care for (suspected) central nervous system malformation or damage in fetus, anencephaly, fetus 5

1–10 of 25

1/3

Procedure/HCPCS/U codes mentioned with coverage classification changes reflected in historyHCPCS|CPT|PLA

0335U	Procedure code referenced; initially added as Procedure code effective 10/01/2022; classified NMN (10/24/2022) then later INV (11/07/2024) along with whole exome sequencing
0336U	Procedure code referenced; added effective 10/01/2022; classified NMN (10/24/2022) then later INV (11/07/2024)
0469U	Added as NMN effective 07/01/2024 (06/12/2024 update); later included in 11/07/2024 update moving related codes to INV
0567U	Added as NMN effective 07/01/2025 (06/10/2025 Administrative Update)
81349	Added on 12/02/2021 Administrative Update; effective 01/01/2022 (no coverage classification in this part)

Procedure/HCPCS/U codes mentioned with coverage classification changes reflected in historyHCPCS|CPT|PLA

0335U	Procedure code referenced; initially added as Procedure code effective 10/01/2022; classified NMN (10/24/2022) then later INV (11/07/2024) along with whole exome sequencing
0336U	Procedure code referenced; added effective 10/01/2022; classified NMN (10/24/2022) then later INV (11/07/2024)
0469U	Added as NMN effective 07/01/2024 (06/12/2024 update); later included in 11/07/2024 update moving related codes to INV
0567U	Added as NMN effective 07/01/2025 (06/10/2025 Administrative Update)
81349	Added on 12/02/2021 Administrative Update; effective 01/01/2022 (no coverage classification in this part)

Provider Actions

Documentation Required

Confirm indication and counseling

Ensure invasive prenatal testing is performed for appropriate indications and that informed pretest and posttest genetic counseling by a genetics-experienced clinician has been provided and documented, including discussion of variants of uncertain significance (VUS), potential nonpaternity, consanguinity, and the possibility of identifying adult-onset disease.

Prior Authorization

Coverage depends on member benefit and medical necessity

Coverage and reimbursement depend on the member's benefit program and eligibility; providers must verify benefit terms and medical necessity for specific tests. Some products may require prior authorization — check the member's benefit information and prior authorization requirements for the applicable product.

Background and Evidence

Evidence summarized in this policy shows that CMA has a higher detection rate of pathogenic chromosomal alterations than karyotyping, with the greatest diagnostic yield in fetuses with malformations identified by ultrasound; professional guidance recommends CMA for fetuses with one or more major structural abnormalities and that CMA can typically replace fetal karyotype. Routine prenatal WES/WGS/NGS is not recommended outside clinical trials because of limitations including longer turnaround times, and higher rates of variants of uncertain significance (VUS), false positives, and false negatives, leading to uncertain clinical validity. Studies and reviews indicate low-pass genome sequencing can improve CNV detection and diagnostic yield compared with CMA in some reports, but WES/WGS remains investigational for routine prenatal diagnosis and may be reserved for selected cases after other testing is noninformative and with expert genetic counseling.

Evidence items (policy citations)

CMA diagnostic yieldHigher detection rate of pathogenic chromosomal alterations compared with karyotyping; greatest yield in fetuses with malformations identified by ultrasound

WES/WGS evidenceInsufficient for routine prenatal diagnosis; may identify abnormalities missed by standard testing in select cases but has limitations (turnaround time, VUS, false positives/negatives)

Wapner NEJM 2012Wapner et al. NEJM 2012: 'Chromosomal microarray versus karyotyping for prenatal diagnosis' cited as key evidence comparing CMA and karyotype

Definitions

Amniocentesis: removal of a small amount of amniotic fluid for fetal genetic testing, typically performed between weeks 15 and 20 of gestation.

Chorionic villus sampling (CVS): sampling of chorionic villi of fetal origin, generally performed after 9 weeks gestation via transcervical or transabdominal approach to obtain placental tissue.

CMA (Chromosomal Microarray Analysis): a method that measures genome-wide gains and losses of DNA (copy number variants, CNVs), detecting submicroscopic chromosomal abnormalities not seen on standard karyotype; CMA identifies deletions and duplications across the genome but does not detect balanced rearrangements.

Revision History

12/02/2021administrative_update

Administrative Update: added new code 81349 effective 01/01/2022.

07/27/2022administrative_update

Administrative Update: added 98 new ICD-10 codes, deleted 6 ICD-10 codes, and added procedure codes 0335U and 0336U effective 10/01/2022.

10/24/2022minor_review

Minor Review (material): designated low-pass genome sequencing as Medically Necessary and whole exome sequencing as Non-Medically Necessary; procedure codes 0335U and 0336U classified as Non-Medically Necessary.

Policy Summary

PayerCapital Bluecross

PolicyInvasive Prenatal (Fetal) Diagnostic Testing

Policy CodePolicy MP 2.278

Change TypeMultiple administrative and minor clinical revisions (see history)

Effective Date12/1/2025

Next Review Date

SourceLink

On This Page

title): "Chromosomal microarray (CMA) Testing"

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Molecular testing for single-gene (Mendelian) disorders

Invasive diagnostic prenatal testing for molecular analysis may be considered medically necessary when pregnancy is identified as high risk for single-gene disorders AND all additional requirements are met.

ALL of the following

Inheritance patterns (ONE of)
- Autosomal dominant: at least one parent has a known pathogenic variant
- Autosomal recessive: both parents are suspected to be carriers or are known carriers
- Autosomal recessive: one parent is clinically affected and the other parent is suspected to be or is a known carrier
- X-linked: a parent is suspected to be or is a known carrier
AND all of the following must be met
- The natural history of the disease is well understood and there is a reasonable likelihood the disease has high morbidity in the homozygous or compound heterozygous state
- The disease has high penetrance
- The genetic test has adequate sensitivity and specificity to guide clinical decision making and residual risk is understood
- An association of the marker with the disorder has been established

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title": "Molecular testing for single-gene (Mendelian) disorders"

ref":

Investigational / Not Medically Necessary

The following uses of invasive prenatal testing are considered investigational (insufficient evidence):

ANY of the following

Prenatal diagnostic whole exome sequencing (with or without trio testing) is investigational
Next-generation sequencing (NGS) in the setting of invasive prenatal testing is investigational
If criteria for molecular analysis for single-gene disorders are not met, invasive diagnostic prenatal testing for molecular analysis is investigational

ref":

Clinical Indications for Prenatal Sequencing (per specialty society guidance)

Situations where prenatal sequencing may be considered (per ISPD/SMFM/Perinatal Quality Foundation position statements):

ANY of the following

Fetus with a major single anomaly or multiple organ system anomalies where no genetic diagnosis found after CMA and clinical genetic expert review suggests single-gene etiology
Fetus with multiple anomaly 'pattern' strongly suggesting a single-gene disorder with no prior genetic testing (CMA should be run before or in parallel)
Personal history of a prior undiagnosed fetus/child affected with major anomalies and recurrence in current pregnancy without a genetic diagnosis after karyotype or CMA
Parental (trio) sequencing may be appropriate for preconception counseling when proband tissue unavailable; sequencing as trio preferred when sequencing performed in absence of fetal phenotype

ref":

Policy determinations (as reflected in revision history)

Policy statements and coverage status changes from policy history:

ALL of the following

Low-pass genome sequencing: classified as Medically Necessary (MN) as of 10/24/2022 (Minor Review).
Whole exome sequencing: was Non-Medically Necessary (NMN) as of 10/24/2022 but updated to Investigational/Not Validated (INV) on 11/07/2024 (policy history notes change from NMN to INV).
Interpretation: whole exome sequencing moved to INV (not covered) on 11/07/2024
Procedure codes 0335U and 0336U: classified as Non-Medically Necessary (NMN) on 10/24/2022; later changed to Investigational/Not Validated (INV) with whole exome sequencing update on 11/07/2024.
Procedure code 0469U: added as NMN effective 07/01/2024 (06/12/2024 update) and subsequently included in the 11/07/2024 update changing related codes to INV.
Procedure code 0567U: added as NMN effective 07/01/2025 (06/10/2025 Administrative Update).

ref":

Billing Rule

Do not assume code listing equals coverage

The presence of a procedure or diagnosis code in the policy's coding section does not denote that the service is covered. Coverage is determined by the member's benefit information and medical necessity for the service.

Documentation Required

Laboratory validation requirements

Tests must be performed in Clinical Laboratory Improvement Amendments (CLIA)-certified high-complexity laboratories. Laboratory-developed tests (LDTs) must meet CLIA standards and be validated by the performing laboratory.

Documentation Required

Use appropriate ICD-10 diagnosis codes for maternal care for suspected fetal abnormalities

When submitting claims for invasive prenatal diagnostic testing, use the appropriate maternal care ICD-10 O35.* code that corresponds to the suspected fetal abnormality from the list provided in this policy part and include that specific O35.* code on the claim.

Use the specific O35.* maternal care ICD-10 code for the suspected fetal abnormality as listed in the policy (examples include O35.02X4, O35.02X5, O35.02X9, O35.10X0, O35.10X1, O35.10X2, O35.10X3, O35.10X4, O35.10X5, O35.10X9, O35.11X0, O35.11X1, O35.11X2, O35.11X3, O35.11X4, O35.11X5, O35.11X9, O35.12X0, O35.12X1, O35.12X2, O35.12X3, O35.12X4, O35.12X5, O35.12X9, O35.13X0, O35.13X1, O35.13X2, O35.13X3, O35.13X4, O35.13X5, O35.13X9, O35.14X0, O35.14X1, O35.14X2, O35.14X3, O35.14X4, O35.14X5, O35.14X9, O35.15X0, O35.15X1, O35.15X2, O35.15X3, O35.15X4, O35.15X5, O35.15X9, O35.19X0, O35.19X1, O35.19X2, O35.19X3, O35.19X4, O35.19X5, O35.19X9, O35.2XX1, O35.2XX2, O35.2XX3, O35.2XX4, O35.2XX5, O35.2XX9, O35.AXX0, O35.AXX1, O35.AXX2, O35.AXX3, O35.AXX4, O35.AXX5, O35.AXX9, O35.BXX0, O35.BXX1, O35.BXX2, O35.BXX3, O35.BXX4, O35.BXX5, O35.BXX9, O35.EXX0, O35.EXX1, O35.EXX2, O35.EXX3, O35.EXX4, O35.EXX5, O35.EXX9, O35.FXX0, O35.FXX1, O35.FXX2, O35.FXX3, O35.FXX4, O35.FXX5, O35.FXX9, O35.GXX0, O35.GXX1, O35.GXX2, O35.GXX3, O35.GXX4, O35.GXX5, O35.GXX9, O35.HXX0, O35.HXX1, O35.HXX2, O35.HXX3, O35.HXX4, O35.HXX5, O35.HXX9

Billing Rule

Apply correct procedure code and coverage classification by effective dates

Report the specific procedure code when billing and be aware of their coverage classification changes and effective dates as noted in the policy history.

0335U
0336U
0469U
0567U
81349

ClinGen/ClinVar partnership 2018ClinGen and ClinVar partnership noted (2018) as resource for variant curation and interpretation

ISPD/SMFM/PQF position statementsJoint ISPD/SMFM/PQF statement (2018) and updated position (2022) provide guidance on prenatal exome/genome sequencing indications and recommend CMA before or in parallel with pES when CNV detection needed

06/12/2024administrative_update

Administrative Update: added procedure code 0469U as Non-Medically Necessary effective 07/01/2024.

11/07/2024minor_review

Minor Review (material): updated prenatal diagnostic whole exome sequencing from Non-Medically Necessary to Investigational and updated related procedure codes (0335U, 0336U, 0469U) accordingly.

06/10/2025administrative_update

Administrative Update: added procedure code 0567U as Non-Medically Necessary effective 07/01/2025.

06/12/2025administrative_update

Administrative Update: removed Benefit Variations Section and updated Disclaimer.

08/14/2025consensus_reviewLatest

Consensus Review: no changes to policy statement.