ModifiedCommunity Health Plan WashingtonPolicy N/A

Concert Genetic Testing: Prenatal Diagnosis

Defines medical necessity criteria and coding guidance for genetic diagnostic tests performed during pregnancy (prenatal) or after pregnancy loss, and describes when chromosomal microarray, karyotype, exome sequencing, targeted panels (e.g., Noonan, skeletal dysplasia) and related testing are considered medically necessary.

Policy Summary

PayerCommunity Health Plan Washington

PolicyConcert Genetic Testing: Prenatal Diagnosis

Policy CodePolicy N/A

Change TypeCoding updatesclinical clarificationsthreshold revision

Effective DateN/A

Next Review DateN/A

Key ActionObtain and document genetic counseling and required prior testing (karyotype and/or microarray) before ordering prenatal exome sequencing.

SourceLink

POLICY UPDATE CHANGES

Expanded coding table to add multiple CPT/HCPCS codes (e.g., 0218U, 81178-81189, 81243, 81251-81259, 81285, 81329, 81231, 81336, 81362-81363, 81401-81407) and removed some prior codes (81271, 81274).

Changed nuchal translucency threshold for Noonan/RASopathy testing to 3.0 mm to align with ACOG guidance and literature.

Noted that whole-exome sequencing and whole-genome sequencing are not recommended routinely for prenatal diagnosis outside research/selected clinical indications until more validation data are available.

CMA primaryACOG recommendation cited

Prior normal karyotype/CMAExome sequencing restriction

POC allowed

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Pregnancy loss CMA coverage

Not coveredGenome sequencing stance

≈6%CMA diagnostic yield (structural anomalies)

≈1.7%CMA yield (normal ultrasound)

Coverage Criteria for Prenatal and Pregnancy-Loss Genetic Testing

Chromosomal Microarray Analysis (CMA) for Prenatal Diagnosis

Covered when ALL of the following are met:

CMA Prenatal: Member has received counseling regarding the benefits and limitations of prenatal screening and diagnostic testing (including chromosome microarray via amniocentesis, CVS, or PUBS).

CMA recommended as primary test when fetal structural abnormalities identified on ultrasound (ACOG).

Conventional Karyotype Analysis for Prenatal Diagnosis

Covered when ALL of the following are met:

Karyotype Prenatal: Member has received counseling regarding the benefits and limitations of prenatal screening and diagnostic testing (including karyotyping via amniocentesis, CVS, or PUBS).

Karyotype may be used but CMA is recommended as the primary test when fetal structural abnormalities are present.

Prenatal Diagnosis via Exome Sequencing

Covered when ALL of the following are met:

Exome Prenatal: Current pregnancy has had a karyotype and/or microarray performed with negative/normal results; alternate etiologies have been considered and ruled out when possible; AND the current pregnancy has either non-immune hydrops fetalis OR two or more major malformations on ultrasound affecting different organ systems.

Pre- and post-test genetic counseling recommended; laboratories offering prenatal ES should have rapid turnaround time. ES is not supported for other indications.

Prenatal Diagnosis via Genome Sequencing

Genome Prenatal: Current evidence does not support prenatal genome sequencing for any indications.

No coverage for prenatal genome sequencing; routine WGS not recommended outside research or specific validated clinical contexts.

Chromosomal Microarray Analysis (CMA) for Pregnancy Loss

Covered when ALL of the following are met:

CMA POC Indication: Member has a history of recurrent pregnancy loss OR has a pregnancy loss at or greater than 20 weeks gestation (intrauterine fetal demise or stillbirth).

AND member has received counseling regarding benefits and limitations of CMA on products of conception.

Conventional Karyotype Analysis for Pregnancy Loss

Covered when ALL of the following are met:

Karyotype POC: Member has a history of recurrent pregnancy loss (defined as two or more failed clinical pregnancies).

Current evidence does not support karyotype on products of conception for other indications.

Prenatal Diagnosis for Noonan Spectrum Disorders/RASopathies

Covered when ALL of the following are met:

Noonan Panel Prenatal: Current pregnancy has had a normal karyotype and/or microarray; AND either (1) first trimester nuchal translucency or cystic hygroma >= 5.0 mm OR (2) nuchal translucency >= 3.0 mm plus one of specified ultrasound findings (distended jugular lymph sacs, hydrops fetalis, polyhydramnios, pleural effusion, or cardiac defects).NT >= 3.0 mm (or >=5.0 mm for isolated large NT)

Use an NGS rasopathy panel; single-gene PTPN11 testing may be used where resources limited.

Prenatal Diagnosis for Skeletal Dysplasias

Covered when ALL of the following are met:

Skeletal Dysplasia Panel Prenatal: Current pregnancy has one or more specified ultrasound findings (e.g., long bones <5th percentile, poor calvarial mineralization, fractures of long bones, bent/bowed bones, poor vertebral mineralization, absent/hypoplastic scapula, equinovarus); AND the panel ordered includes at minimum COL1A1, COL1A2, COL2A1, FGFR3.long bone <= 5th percentile or >3 SD below mean

Refer to centers with skeletal dysplasia expertise; multigene NGS panels have high diagnostic yield.

Initial diagnostic testing (CMA, ES, WGS)

Covered when ALL of the following are met (where specified by specialty guidance):

CMA for structural anomalies: When a fetal structural abnormality is detected on prenatal ultrasound, chromosomal microarray analysis is recommended as the primary diagnostic test, replacing conventional karyotype; CMA identifies clinically significant abnormalities in approximately 6% of fetuses with a normal karyotype.

ACOG practice bulletin supports CMA as primary test.

CMA availability for invasive testing: CMA should be offered to any patient choosing to undergo invasive diagnostic testing even when ultrasound is normal, as CMA detection rate in that setting is approximately 1.7%.

ACOG practice bulletin

Exome sequencing (ES): ES may be considered for fetuses with ultrasound anomalies when CMA and karyotype are non-diagnostic; if a specific disorder is suspected, single-gene or targeted panel testing should be performed first; pre- and post-test genetic counseling recommended and laboratories should provide rapid turnaround time.

ACMG points-to-consider; detection rate proportional to phenotype severity.

Pregnancy loss evaluation

Covered when ALL of the following are met:

CMA for pregnancy loss/stillbirth: Chromosomal microarray analysis of fetal tissue (amniotic fluid, placenta, or products of conception) is recommended in the evaluation of intrauterine fetal death or stillbirth when further cytogenetic analysis is desired due to increased likelihood of obtaining results and improved detection of causative abnormalities.

ACOG/SMFM Committee Opinion supports CMA for IUFD/stillbirth.

Karyotype in recurrent pregnancy loss: Evaluation for recurrent pregnancy loss (defined as two or more failed clinical pregnancies) may include karyotypic analysis of products of conception as part of the workup.

ASRM guidance: evaluate after two losses.

Targeted disorder-specific testing

Covered when ALL of the following are met:

Noonan/RASopathy testing: Fetal testing is indicated for suspected rasopathies when ultrasound findings meet the policy criteria (e.g., NT >= 3.0 mm with additional anomalies or NT >=5.0 mm isolated after excluding chromosomal abnormalities); use an NGS rasopathy panel or single-gene testing (PTPN11) where resources limited.NT >= 3.0 mm (policy aligns with ACOG definition of enlarged NT)

Cohort study and GeneReviews support clinical features and testing approach.

Skeletal dysplasia testing: Fetuses with long bone measurements <=5th centile or >3 SD below mean or other concerning skeletal ultrasound findings should be evaluated at specialized centers; multigene NGS panels including COL2A1, FGFR3, COL1A1, COL1A2 are recommended given high diagnostic yield (≈42% in one cohort).long bone <=5th centile or >3 SD below mean

Krakow guideline and panel study support gene list and yield.

Current evidence does not support use of chromosomal microarray, conventional karyotype, exome sequencing, genome sequencing, targeted panels, or related tests for indications other than those explicitly described in the policy sections. Tests performed outside the listed medically necessary indications may be denied and are not supported by this evidence base.

Providers should ensure that the specific clinical indications and prerequisite testing described in each section are documented (e.g., counseling provided, prior normal karyotype and/or CMA when required) before ordering or submitting claims for these tests.

Routine use of whole-genome sequencing (WGS) or routine whole-exome sequencing (ES) for prenatal diagnosis is not recommended outside of clinical research or highly selected, validated clinical indications. National guidance (ACOG/SMFM and ACMG) supports restricting routine WGS/ES use in prenatal settings until further validation and larger prospective data are available.

When fetal ES is considered, it should follow the documented prerequisites (e.g., prior negative/normal karyotype and/or CMA) and include pretest genetic counseling and laboratory processes that support rapid turnaround times appropriate for prenatal decision-making.

Coverage decisions and administration of benefits under this policy are subject to all terms, conditions, exclusions, and limitations of the member's coverage documents (for example, evidence of coverage, certificate of coverage, policy, or contract of insurance). This clinical policy is a guide to medical necessity and does not guarantee payment; providers must follow Health Plan-level procedures and applicable legal/regulatory requirements.

Current evidence does not support prenatal genome sequencing for any indications. Prenatal genome sequencing is considered not medically necessary and is not covered under this policy.

Outside the specific diagnostic scenarios described in the policy (for example, ES following nondiagnostic CMA/karyotype in fetuses with multiple major malformations or non-immune hydrops), routine use of WGS/ES for other prenatal indications is not recommended given limited validation data and uncertain clinical utility.

When considering high-complexity sequencing in prenatal care, providers must document required prior testing and counseling and recognize that testing without these prerequisites may be considered unsupported by current evidence.

Specific Covered Indications

CMA for prenatal diagnosis when counseling provided and indication met (primary test when fetal structural abnormalities present)

Covered when ALL of the following are met:

CMA primary test for fetal anomalies: When fetal structural anomalies are identified on ultrasound, chromosomal microarray analysis is the recommended primary diagnostic test and should replace conventional karyotype; CMA detects clinically significant copy number variants in approximately 6% of fetuses with a normal karyotype.

ACOG practice bulletin #162/#226 support this recommendation.

CMA offered for invasive testing: CMA should be made available to any patient choosing invasive diagnostic testing even if ultrasound is normal, as CMA detection rate in that setting is approximately 1.7%.

ACOG practice bulletin

ES after nondiagnostic CMA/karyotype: Exome sequencing may be considered when CMA and karyotype are nondiagnostic for fetuses with anomalies; pretest counseling by a genetics professional and rapid laboratory turnaround time are recommended.

Coding and Reimbursement References

Referenced CPT/Proprietary codes for prenatal and pregnancy-loss testingmixed

81228	Chromosomal microarray analysis (example listed)
81229	Chromosomal microarray analysis (example listed)
81265	Chromosomal microarray analysis/additional
88235	Amniotic fluid/chorionic villus/peripheral blood cell culture; prenatal cytogenetic studies (example)
0469U	Proprietary/test-specific lab code (example)
81415	Exome sequencing, interpretation and report (proband only)
81416	Exome sequencing, interpretation and report, each additional family member
81425	Genome sequencing, large-scale sequencing (example listed)
81426	Genome sequencing, additional reporting (example listed)
0335U	Proprietary prenatal genome test code (example)

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1/2

Prior-authorization listed CPT/0300-series codes (policy callout)mixed

81228	Chromosomal microarray analysis (example listed)
81229	Chromosomal microarray analysis (example listed)
81265	Chromosomal microarray analysis/additional
88235	Amniotic fluid/chorionic villus/peripheral blood cell culture; prenatal cytogenetic studies (example)
0469U	Proprietary/test-specific lab code (example)
81415	Exome sequencing, interpretation and report (proband only)
81416	Exome sequencing, interpretation and report, each additional family member
81425	Genome sequencing, large-scale sequencing (example listed)
81426	Genome sequencing, additional reporting (example listed)
0335U	Proprietary prenatal genome test code (example)

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1/2

ICD-10 codes referencedICD-10

O26.2	Pregnancy-related care codes referenced
O28.3	Fetal genetic testing in pregnancy
O35.8XX0	Maternal care for known or suspected fetal abnormality, unspecified trimester
O03	Spontaneous abortion
Z37	Outcome of delivery; used with pregnancy loss testing
Q00-Q99	Congenital malformations, deformations and chromosomal abnormalities (range)
Z14.8	Genetic carrier and related testing codes referenced

CPT codes for targeted prenatal panels (Noonan, skeletal dysplasia)CPT

81404	Targeted gene panel (e.g., Noonan spectrum)
81405	Targeted gene panel (larger)
81406	Targeted multi-gene panel
81407	Targeted multi-gene panel
81479	Unlisted molecular pathology procedure
81442	MGPT single gene full sequencing (example)

Updated/Added molecular and panel testing codesmixed

0218U	Proprietary code added to policy reference table
81178-81189	Range of molecular pathology sequence analysis codes added
81243	Molecular test code added
81251-81259	Gene-specific testing codes added
81285	Gene testing code added
81329	Genetic code added
81231	Genetic code added
81336	Genetic code added
81362-81363	Genetic codes added
81401-81407	Panel/sequence codes added

inv-21: Nuchal translucency (NT) threshold used to trigger testing for Noonan/RASopathy guidance

NT threshold for Noonan/RASopathy testingNuchal translucency (NT) >= 3.0 mm

Higher-threshold option from cohort studyNT >= 5.0 mm recommended for testing when NT is the sole finding (Stuurman et al., cohort)

ACOG definition of enlarged NTACOG defines enlarged NT as 3.0 mm or more (or >99th percentile for CRL)

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization may be required for listed CPT and related codes. Providers should verify payer-specific prior authorization requirements before ordering tests to avoid claim denials or delays.

Affected CPT/HCPCS examples: 81415, 81416, 81425, 81426, 81228, 81229, 81265, 81243, 81251-81259, 81178-81189, 0469U, 0335U, 0336U
Newly added single-gene and panel test codes (see policy coding table) may require prior authorization

Prior Authorization

Prior Authorization Guidance

Clinical policy criteria are used to determine coverage and prior authorization decisions. Providers must follow payer rules for submission, including completing any required prior authorization forms and supplying supporting clinical documentation that demonstrates the member meets the policy criteria.

Submit clinical indication, relevant ultrasound findings, prior test results (karyotype and/or CMA), and evidence of counseling when requesting prior authorization
Tests not meeting policy criteria or submitted without required documentation may be denied

Definitions and Abbreviations

inv-37: Definition — prenatal diagnostic testing

DefinitionDiagnostic genetic testing performed during pregnancy (via amniocentesis, CVS, or PUBS) to identify fetal genetic conditions when the fetus is at increased risk; decisions should be made jointly by the parents and clinician with strong recommendation for genetic counseling.

Common proceduresIncludes testing on samples obtained by amniocentesis, chorionic villi sampling (CVS), or percutaneous umbilical cord blood sampling (PUBS)

Use casesUsed to identify genetic conditions in fetuses and to evaluate causes of isolated or recurrent pregnancy loss (miscarriage, IUFD, stillbirth)

inv-38: Definition — CMA (chromosomal microarray analysis) description and role

DefinitionChromosomal microarray analysis (CMA) detects copy number variants smaller than the resolution of conventional karyotype and is recommended as the primary diagnostic test when fetal structural abnormalities are detected on ultrasound.

Eligibility Requirements and Operational Criteria

Eligibility for prenatal and pregnancy-loss genetic testing should be determined jointly by the patient(s) and treating clinician, with strong recommendation for genetic counseling. This policy defines specific clinical eligibility criteria in each section (e.g., fetal structural anomalies, recurrent pregnancy loss, or defined ultrasound findings for disorder-specific panels) and refers providers to the full criteria for documentation requirements.

Providers should reference the policy’s coding and operational updates when submitting authorizations and claims, including newly added CPT/HCPCS and proprietary codes in the reference table. Prior authorization may be required for listed codes per Health Plan procedures.

Operational and coding updates have been made to the policy reference tables. Providers should use the updated code lists (including newly added molecular and panel test codes) when requesting prior authorization or submitting claims and verify whether prior authorization is required for these specific codes.

Documentation accompanying authorization requests should include the clinical indication, evidence of counseling, and any required prior testing (for example, results of karyotype or CMA when applicable).

Prenatal exome sequencing and disorder-specific panels have defined eligibility prerequisites: ES requires a prior negative/normal karyotype and/or microarray and presence of either non-immune hydrops fetalis or two or more major malformations on ultrasound. Targeted panels for Noonan spectrum disorders and skeletal dysplasias require prior normal karyotype/CMA and the ultrasound findings specified in the criteria (including NT thresholds and listed skeletal measurements).

Skeletal dysplasia panels must include, at minimum, the genes COL1A1, COL1A2, COL2A1, and FGFR3 as specified in the policy.

Not Covered / Experimental Interventions

Prenatal genome sequencing is not supported for any indications. This policy lists prenatal genome sequencing as not medically necessary and does not cover WGS for prenatal diagnostic use.

Routine whole-genome sequencing (WGS) and whole-exome sequencing (ES) for prenatal diagnosis across indications is not recommended outside clinical research or select validated clinical scenarios. National society guidance emphasizes limiting routine use until additional peer-reviewed validation studies are available.

When ES is used in prenatal care, it should follow established prerequisites and include pretest counseling and laboratory processes capable of rapid turnaround.

Background and Evidence Summary

Genetic testing during pregnancy and after pregnancy loss is used to identify fetal genetic conditions or to evaluate causes of miscarriage, intrauterine fetal demise (IUFD), and stillbirth. Testing decisions should be made jointly by the mother/parents and the treating clinician, and genetic counseling is strongly recommended to facilitate informed decision-making.

Chromosomal microarray analysis (CMA) detects copy number variants smaller than the resolution of conventional karyotype and is recommended as the primary diagnostic test when fetal structural abnormalities are identified by ultrasound. CMA and karyotype testing require prior counseling about benefits and limitations before invasive sampling (amniocentesis, CVS, PUBS).

inv-49 (evidence context): CMA diagnostic yield and context for fetal structural anomalies vs normal ultrasound (supporting evidence)

Covered when ALL of the following are met:

CMA diagnostic yield evidence: ACOG states CMA identifies clinically significant chromosomal abnormalities in approximately 6% of fetuses with structural abnormalities and normal karyotype, supporting CMA as primary test for fetal structural anomalies.

Policy uses this evidence to justify CMA-first approach for anomalies.

inv-52: Evidence contexts for use of ES/WGS and NGS panels (literature and guideline citations)

Policy Summary

PayerCommunity Health Plan Washington

PolicyConcert Genetic Testing: Prenatal Diagnosis

Policy CodePolicy N/A

Change TypeCoding updatesclinical clarificationsthreshold revision

Effective DateN/A

Next Review DateN/A

Key ActionObtain and document genetic counseling and required prior testing (karyotype and/or microarray) before ordering prenatal exome sequencing.

SourceLink

On This Page

Genome sequencing (WGS): WGS has shown diagnostic promise in a single study (diagnostic rate 19.8%) but routine use for prenatal diagnosis is not recommended outside research or selected clinical indications until further validation data are available.

ACOG/SMFM committee opinion; more prospective studies needed.

ACMG points-to-consider and detection rate proportional to phenotype severity.

WGS not routine: Whole-genome sequencing has shown diagnostic promise in preliminary studies (e.g., single study diagnostic rate ~19.8%) but routine use for prenatal diagnosis is not recommended outside research or selected clinical indications until further validation.

ACOG/SMFM committee opinion; Zhou et al. 2021 evidence context.

Prenatal exome sequencing for pregnancies with prior normal karyotype/microarray and either non-immune hydrops fetalis or two or more major malformations on ultrasound

Covered when ALL of the following are met:

Prenatal ES criteria: Current pregnancy has had karyotype and/or microarray performed with negative/normal results; alternate etiologies considered/ruled out when possible; AND pregnancy presents with either non-immune hydrops fetalis OR two or more major malformations on ultrasound affecting different organ systems.

Pretest counseling by a genetics professional and rapid TAT recommended; detection rate proportional to phenotype severity.

CMA on products of conception for recurrent pregnancy loss or pregnancy loss >=20 weeks gestation

Covered when ALL of the following are met:

CMA POC indications: Member has recurrent pregnancy loss (two or more failed clinical pregnancies) OR pregnancy loss at or greater than 20 weeks gestation (IUFD/stillbirth); AND CMA is being performed on products of conception or fetal tissue.

ACOG/SMFM recommends CMA for evaluation of IUFD/stillbirth due to higher yield than cytogenetics.

Targeted prenatal panels for Noonan spectrum disorders or skeletal dysplasias when specified ultrasound and prior testing criteria are met

Covered when ALL of the following are met:

Targeted prenatal Noonan/Skeletal panels: Testing with targeted prenatal gene panels for suspected Noonan spectrum disorders or skeletal dysplasias is covered when specified ultrasound findings and prior testing criteria are met (e.g., prior normal karyotype/CMA). Panels should include relevant genes (Noonan/rasopathy panels or skeletal genes such as COL1A1, COL1A2, COL2A1, FGFR3).NT >= 3.0 mm for Noonan-related consideration; long bone <=5th centile for skeletal dysplasia consideration

Use NGS panels; consider single-gene testing (PTPN11) in limited-resource settings.

Fetal structural anomalies identified on ultrasound — CMA primary test; invasive diagnostic testing when chosen by patient; ES when CMA/karyotype nondiagnostic in fetuses with anomalies (includes diagnostic yield context)

Covered when ALL of the following are met:

Fetal structural anomalies pathway: When fetal structural anomalies are identified on ultrasound, chromosomal microarray analysis is the primary diagnostic test; invasive diagnostic testing (amniocentesis, CVS, PUBS) should be offered and CMA performed if chosen by the patient. If CMA and karyotype are nondiagnostic, exome sequencing may be considered.

CMA detects ~6% additional findings when karyotype normal; CMA detects ~1.7% in patients with normal ultrasound and normal karyotype.

Evaluation of intrauterine fetal death or stillbirth — CMA of fetal tissue recommended (higher yield than cytogenetics)

Covered when ALL of the following are met:

IUFD/stillbirth evaluation: Chromosomal microarray analysis of fetal tissue (amniotic fluid, placenta, or products of conception) is recommended in the evaluation of intrauterine fetal death or stillbirth when cytogenetic analysis is desired due to increased likelihood of obtaining results and improved detection of causative abnormalities.

ACOG/SMFM Committee Opinion supports CMA over conventional cytogenetics in this context.

Suspected Noonan/RASopathy and suspected skeletal dysplasias — use NGS panels or single-gene testing when appropriate

Covered when ALL of the following are met:

Noonan/RASopathy and skeletal dysplasia testing: Suspected Noonan/RASopathy or skeletal dysplasia based on ultrasound findings should be evaluated with NGS panels or single-gene testing as appropriate; Noonan consideration when NT and/or associated anomalies meet criteria; skeletal dysplasia panels should include core genes like COL1A1/2, COL2A1, FGFR3.NT >= 3.0 mm (ACOG definition); long bone <=5th centile or >3 SD below mean for skeletal dysplasias

Evidence and cohort studies support panel use and diagnostic yields.

Prenatal diagnosis contexts (structural anomalies, skeletal dysplasias, rasopathies, NIHF) as discussed in cited literature supporting use of ES/WGS/NGS panels

Covered when ALL of the following are met:

Specialty guidance contexts: Prenatal diagnosis of fetal structural anomalies, skeletal dysplasias, rasopathies, and non-immune hydrops fetalis is addressed in specialty guidance and literature supporting use of fetal exome/WGS and targeted NGS panels in these specific contexts.

References include ACMG points-to-consider, ACOG/SMFM committee opinions, and diagnostic yield studies.

Documentation Required

Prenatal Exome Sequencing Requires Prior Normal/Negative Karyotype and/or CMA

Prenatal exome sequencing is allowed only when prior testing has been performed and is negative/normal. Providers must document prior karyotype and/or chromosomal microarray (CMA) results in the medical record and include this documentation with any authorization request.

Required prior testing: negative/normal karyotype and/or CMA before prenatal ES is considered
Include lab reports or official result summaries showing negative/normal findings

Documentation Required

Documentation Must Include Evidence of Counseling and Clinical Rationale

Documentation submitted with claims and prior authorization requests must include evidence of counseling regarding benefits, limitations, and potential outcomes of prenatal testing, as well as the clinical rationale for testing.

Pretest counseling: note that counseling occurred and by whom (genetics professional preferred)
Post-test counseling: documentation of follow-up counseling is recommended and may be requested
Include documentation of consideration and exclusion of alternate etiologies where applicable

Note

Regulatory Alignment and Documentation

When state Medicaid, Medicare NCD/LCD, or other regulatory requirements differ from this clinical policy, the applicable legal or regulatory requirement takes precedence. Providers should reference the member's plan documents and relevant NCDs/LCDs when preparing prior authorization requests or responding to coverage determinations.

Medicaid: state Medicaid provisions override this policy where conflicts exist
Medicare: review applicable NCDs, LCDs, and Medicare Coverage Articles on CMS.gov prior to applying policy criteria

Denial Risk

Exome Sequencing Allowed Only After Prior Testing; Genome Sequencing Not Supported

Exome sequencing is allowed only after prior testing (karyotype and/or microarray) is negative/normal and when the pregnancy meets specified ultrasound or clinical findings as outlined in the policy (e.g., non-immune hydrops fetalis or ≥2 major malformations affecting different organ systems). Genome sequencing is not supported for routine prenatal diagnosis.

Indications for prenatal ES include: non-immune hydrops fetalis, or two or more major malformations on ultrasound affecting different organ systems
Routine prenatal genome sequencing (WGS) is not supported outside of research or specified policy exceptions

Note

Provider Responsibility and Claims

Providers are responsible for ensuring that testing and claims comply with this clinical policy and with member plan terms. This policy is guidance and does not guarantee payment; providers should include complete documentation and follow payer administrative processes when ordering tests.

Tests performed outside listed medically necessary indications or without required documentation may be denied
Final coverage is determined by member plan documents, terms, and conditions

Diagnostic yieldCMA identifies clinically significant chromosomal abnormalities in ~6% of fetuses with structural anomalies and normal karyotype; ~1.7% yield when ultrasound and karyotype are normal but invasive testing performed

RoleReplaces conventional karyotype as primary test for prenatal diagnosis of fetal structural abnormalities and should be available to patients choosing invasive testing

inv-39: Definition — Amniocentesis

DefinitionAmniocentesis is a procedure in which a sample of amniotic fluid is removed from the uterus for prenatal diagnostic testing.

Typical useSample used for karyotype, chromosomal microarray, and other diagnostic molecular tests as indicated

Sampling routeTransabdominal needle aspiration of amniotic fluid under ultrasound guidance

inv-40: Definition — Chorionic villi sampling (CVS)

DefinitionChorionic villi sampling (CVS) is a procedure where a sample of chorionic villi is removed from the placenta for prenatal diagnostic testing.

Typical useAllows earlier prenatal diagnostic testing compared with amniocentesis and can be used for karyotype, CMA, or targeted molecular testing

Sampling routeTranscervical or transabdominal sampling of placental tissue under ultrasound guidance

inv-41: Definition — Major malformations

DefinitionMajor malformations are structural defects that have a significant effect on function or appearance; they may be lethal or associated with severe or moderate immediate or long-term morbidity.

Examples by organ systemGenitourinary (e.g., renal agenesis), cardiovascular (complex heart malformations), musculoskeletal (osteogenesis imperfecta), CNS (anencephaly), body wall (omphalocele), respiratory (congenital lung malformation)

Relevance to testingPresence of two or more major malformations on ultrasound can meet criteria for consideration of prenatal exome sequencing (with prior normal karyotype/CMA)

inv-42: Definition — Percutaneous umbilical cord blood sampling (PUBS)

DefinitionPercutaneous umbilical cord blood sampling (PUBS) is a procedure where a sample of fetal blood is extracted from the vein in the umbilical cord for prenatal diagnostic testing.

Typical useUsed when fetal blood is required for cytogenetic or molecular testing and may be used when amniocentesis/CVS are not feasible or inconclusive

Sampling routeTransabdominal needle aspiration of the umbilical cord under ultrasound guidance

inv-43: Definition — Recurrent pregnancy loss (RPL)

DefinitionRecurrent pregnancy loss (RPL) is defined as two or more failed clinical pregnancies, including a current loss if applicable.

Implication for testingCMA on products of conception or karyotype may be considered in evaluation of recurrent pregnancy loss to identify chromosomal causes

Examples of losses includedIncludes miscarriages, intrauterine fetal demise (IUFD), and stillbirth when meeting the gestational criteria

inv-44: Definition — Fetal exome/WGS

DefinitionFetal exome sequencing (ES) and whole genome sequencing (WGS) are next-generation sequencing tests performed on fetal DNA obtained via invasive sampling (amniocentesis, CVS, PUBS) to detect single-gene and other sequence-level variants.

Use and limitationsES may be considered for fetuses with ultrasound anomalies when karyotype and CMA are non-diagnostic; WGS shows diagnostic promise but is not recommended routinely outside research or select clinical indications.

Counseling and turnaroundPretest counseling by a genetics professional is recommended for fetal ES/WGS; laboratories offering prenatal ES should have rapid turnaround times defined.

Certain tests require a stepwise testing approach: exome sequencing is allowed only after prior karyotype and/or CMA are negative/normal. For fetal structural anomalies, CMA (replacing karyotype as the primary test) is recommended first; ES may be considered when CMA/karyotype are nondiagnostic. If a specific monogenic diagnosis is suspected, single-gene or targeted panel testing should be performed first.

Providers should document prior testing results and that alternative etiologies have been considered when requesting ES or other high-complexity sequencing tests.

ES/WGS evidence contexts: ACMG and ACOG/SMFM guidance and peer-reviewed studies indicate ES may be valuable when CMA/karyotype nondiagnostic in fetuses with anomalies and that WGS shows promise but requires further validation; specialized literature documents diagnostic yields and contexts for use of ES/WGS and NGS panels.

References include ACMG points-to-consider and Zhou et al. 2021 WGS study.