Description
Genetic disease is defined as a morbid disorder that is caused by an abnormality in human genetic material. Genetic defects find their most varied expression in disruptions of the intricate chemistry that underlies human structure and metabolism. These manifestations range from such well-known conditions as Down’s syndrome and phenylketonuria (PKU) to very rare conditions. Certain ethnic groups are at increased risk for specific genetic disorders (e.g., sickle cell anemia, thalassemia, Tay-Sachs disease, Canavan’s disease). Major birth defects are apparent in 2-3% of live births with chromosome abnormalities occurring in about 0.5% of all live births.

Preconception and prenatal genetic counseling entails screening prospective parents on the basis of diagnostic tests and family studies. Testing can be performed by various techniques; such as entire gene sequencing, single-strand conformation analysis, conformation sensitive gel electrophoresis assay for truncated protein, and specific mutation assay. Each technique has its own strengths and weaknesses, depending on the disease/condition being tested. In addition to studying chromosomes or genes, genetic testing in a broader sense includes biochemical tests for the presence or absence of key proteins that signal aberrant genes.

Preconception or prenatal genetic screening can be targeted risk-based carrier screening, or non-targeted panel tests. Targeted risk-based carrier screening identifies single genes for individuals or their partners who are known to be at a higher risk of having or carrying specific X-linked or autosomal recessive disease, and therefore, are at an increased risk of having offspring with that condition. Non-targeted panel tests are done regardless of an individual’s risk and include any number of genes.

Preconception, or carrier, genetic counseling and testing are conducted before conception occurs, through analysis of family and parental history and, if indicated, parental testing. It is intended to estimate the risk of a fetus having a genetic defect to assist with reproductive decision making. Individuals who are identified for increased risk may choose in-vitro fertilization with preimplantation genetic testing, the use of donor gametes, adoption, or may pursue no action at all.

Prenatal genetic counseling and testing is conducted after conception with the intent of identifying parental or fetal genetic defects through analysis of family and parental history and if indicated, parental or fetal testing (e.g., amniocentesis, chorionic villus sampling, fetal ultrasound, maternal multiple marker serum sampling, periumbilical blood sampling/cordocentesis, or placental biopsy).

Policy

1. Based upon our criteria and assessment of the peer-reviewed literature, genetic testing for inheritable diseases in individuals seeking preconception or prenatal care when offered in a setting with health care professionals who are adequately trained to provide appropriate pre- and post-test counseling and performed by a qualified laboratory, has been medically proven to be effective and therefore, is considered MEDICALLY NECESSARY when ALL of the following criteria are met:
   1. There is reasonable expectation, based on family history, pedigree analysis, risk factors, and/or signs or symptoms that an increased risk of a genetically inherited condition exists;
   2. Screening for conditions not considered a component of routine care will require documentation of genetic counseling. Documentation showing the completion of counseling establishing the risk of carrier status, the natural history of the relevant disorder(s), prospects for treatment and cure, availability of prenatal genetic testing, and reproductive options is necessary.
   3. The testing method is considered a proven method for the identification of a genetically linked disease; and
   4. The test results will influence decisions concerning disease treatment or prevention
2. Based upon our criteria and assessment of the peer-reviewed literature, including the American College of Obstetricians and Gynecologists and the American College of Medical Genetics, preconception or prenatal carrier screening for spinal muscular atrophy (SMA) (CPT 81337, 81403, 81329, 81336, 81401, 81405, or 0236U) and Cystic Fibrosis (CPT 81221, 81223, 81222, 81220, or 81224) is considered MEDICALLY NECESSARY as part of routine care.
3. Preconception or prenatal carrier screening for fragile X or fragile X-related disorders (CPT 81243 or 81244) is considered medically necessary after genetic counseling in women identified with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome.
4. Preconception or prenatal carrier screening for hemoglobinopathies via HBA1, HBA2 (81257, 81258), or HBB (81361, 81362) targeted variant analysis is considered MEDICALLY NECESSARY for individuals with a family history of a hemoglobinopathy or an abnormal screening complete blood count.
   1. Note: If a member’s reproductive partner is known to be a carrier of a hemoglobinopathy, via genetic testing results and/or hematologic screening results, the more appropriate test for the member is likely HBA1, HBA2, or HBB Sequencing and/or Deletion/Duplication Analysis via HBA1, HBA2 (81259, 81269), or HBB (81363, 81364).
5. Preconception or prenatal carrier screening is considered MEDICALLY NECESSARY for individuals of Eastern and Central European Jewish (Ashkenazi) descent for Tay–Sachs disease (TSD), Canavan disease, cystic fibrosis and familial dysautonomia via Ashkenazi Jewish associated disorders, genomic sequence analysis panel (CPT 81412).
6.  Preconception or prenatal carrier screening for inherited disorders without family history or other identified risk factors is considered NOT MEDICALLY NECESSARY as part of routine care.
7. Based upon our criteria and assessment of the peer-reviewed literature, non-targeted/ multi-gene panel testing for preconception or prenatal carrier screening (e.g., Genesys Carrier Panel - 0400U; Horizon Advanced Carrier Screening, Natera (81243, 81257, 81329, 81443); Myriad Foresight Screening (81329, 81443), Myriad, SEMA4 Elements (81443), Unity Carrier Screen (0449U))** is considered NOT MEDICALLY NECESSARY as it is not considered part of routine care.
   1. **Please note the list above may not be all-inclusive.

Coverage statement on Bundling/Unbundling: An accurate description of the test being requested is required. Unbundling is the submission of multiple procedure codes for a group of specific procedures that are components of a single comprehensive code. For the purpose of establishing medical necessity, the CPT code that most accurately depicts the comprehensive testing performed will be considered.

Policy Guidelines
The Health Plan and its employees adhere to all State and Federal laws concerning the confidentiality of genetic testing and the results of genetic testing. All records, findings and results of any genetic test performed on any person shall be deemed confidential and shall not be disclosed without the written informed consent of the person to whom such genetic test relates. This information shall not be released to any person or organization not specifically authorized by the individual subject of the test or in compliance with applicable law.

Genetic testing is appropriate only when performed by a qualified laboratory certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and offered in a setting with adequately trained health care professionals who are qualified to provide appropriate pre- and post-test counseling.

Genetic testing is contract dependent. Coverage only applies to members with a valid contract; coverage is not provided for family members without a valid contract.

Supporting documentation required:

The following factors will be considered when determining the medical appropriateness of a genetic test:

• There must be reasonable expectation based on family history, pedigree analysis, risk factors, and/or symptomatology that a genetically inherited condition exists. Autosomal recessive disorders may be present without a family history.
• The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with the occurrence of the disease, and the analytical and clinical validity of the test must be established.
• The clinical utility of the test must be established (e.g., test results will influence decisions concerning disease treatment or prevention).
• Genetic testing should be performed for management or treatment of the patient and not only for knowledge purposes. Documentation should demonstrate how test results will impact treatment or medical management.
• When there is family history or phenotype suggestive of a specific syndrome, results of targeted testing for the mutation associated with the syndrome should be documented prior to any panel testing. If targeted testing has not been performed, rationale as to why panel testing is medically necessary should be documented.

Preconception and prenatal carrier testing should not be completed more than once per lifetime.

If genetic etiology for spontaneous abortions is suspected, documentation of karyotyping results for both partners are required for non-targeted/multi-gene panel testing requests.

A first-degree relative is a blood relative who shares approximately 50% of an individual’s genes (parents, full siblings, and children). A second-degree relative is a blood relative who shares approximately 25% of an individual’s genes (grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings). A third-degree relative is a blood relative who shares approximately 12.5% of an individual’s genes (great-grandparents, great-grandchildren, great-aunts, great-uncles, first cousin, and grand-niece or nephew.)

All preconception and prenatal testing must be rendered in a setting with health care professionals who are adequately trained to provide the appropriate pre- and post-test counseling and testing must be performed by a laboratory qualified to perform the testing.

If the genetic test is being done for knowledge only, and that knowledge will not alter management or treatment of the patient or family member, then the testing is not medically appropriate.

Coverage of preconception and prenatal genetic testing and counseling are contract dependent.

Rationale
The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with a high positive predictive value of the occurrence of a disease. Analytical sensitivity and specificity of a genetic test must be of such a level that the test results can and will be used in making treatment decisions. Information on the risks and benefits of genetic testing must be presented fully and objectively without coercion to persons contemplating genetic testing.

Because fetal gene mutations can be either inherited from a parent or acquired by exposure to environmental stresses such as radiation or toxins, in utero testing of an at-risk fetus offers partners an additional opportunity to make informed choices regarding reproductive options. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 88 (2007), Invasive Prenatal Testing for Aneuploidy (Down Syndrome), issued Level A recommendations. Among the recommendations was that women found to have increased risk of aneuploidy with first-trimester screening should be offered genetic counseling and the option of CVS or second-trimester amniocentesis.

In 2001, the American College of Obstetricians and Gynecologists and the American College of Medical Genetics introduced guidelines for prenatal and preconception carrier screening for cystic fibrosis (CF). The guidelines recommended that screening for CF be performed as part of routine obstetric practice for all patients. Given that CF screening has been a routine part of reproductive care for women since 2001, it is prudent to determine if the patient has been previously screened, before ordering CF screening that may be redundant. If a patient has been screened previously, CF screening results should be documented but the test should not be repeated.

In March 2017, the ACOG Committee on Genetics recommended that information about genetic carrier screening should be provided to every pregnant woman. Carrier screening and counseling ideally should be performed before pregnancy. The committee noted that it is important to obtain the family history of the patient and, if possible, her partner as a screening tool for inherited risk. Carrier screening for a particular condition generally should be performed only once in a person’s lifetime and the results should be documented in the patient’s health record.

In March 2017, ACOG Committee on Genetics recommendations also indicated that screening for spinal muscular atrophy should be offered to all women who are considering pregnancy or are currently pregnant.

In March 2017, ACOG Committee on Genetics recommended fragile X permutation carrier screening for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome and who are considering pregnancy or are currently pregnant. Certain autosomal recessive disease conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent. ACOG has recommended that individuals of Eastern European Jewish ancestry be offered carrier screening for Tay–Sachs disease (TSD), Canavan disease, and cystic fibrosis as part of routine obstetric care. They recently recommended additional carrier screening for familial dysautonomia. All of these tests have a high sensitivity in the Jewish population. The prevalence of these disorders in non-Jewish populations, except for TSD and cystic fibrosis, is unknown. The sensitivity of these carrier tests in non-Jewish populations has not been established. The mutations may be different and more diverse. Consequently, when only one partner is Jewish, it is difficult to assess the risk of having an affected offspring. Therefore, carrier screening of the non-Jewish partner is of limited value.

ACOG has also recommended that women with a specific family history of hereditary disorders (e.g., fragile X) or other clinical features (e.g., unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency) be candidates for genetic counseling carrier screening for that particular disorder or syndrome.

NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guidelines (V.1.2025) states "Although the use of prenatal diagnosis or PGT is relatively well established for severe hereditary disorders with very high penetrance and/or early onset (eg, Fanconi anemia), its use in conditions associated with lower penetrance and/or later onset (eg, hereditary breast or ovarian cancer syndrome) remains somewhat controversial from both an ethical and regulatory standpoint....Successful births have been reported with the use of PGT and IVF in carriers of a BRCA1/2 pathogenic or likely pathogenic variant, but data in the published literature are still very limited. In addition, data pertaining to long-term safety or outcomes of PGT and assisted reproduction in carriers of a pathogenic or likely pathogenic variant are not yet available."

In addition, NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic guidelines (V.1.2025) recommends that for individuals of Ashkenazi Jewish descent, complete gene panel analysis including specific AJ founder mutations should be considered based on family history; testing limited to AJ founder testing may be appropriate for families segregating known mutations, or in population screening in which a negative test is followed by more complete testing depending on personal and/or family history.

The American Society of Reproductive Medicine (2012) recommends karyotypic analysis of products of conception which may be useful in the setting of ongoing therapy for recurrent pregnancy loss.

In 2020, ACOG reaffirmed its 2016 recommendation that chromosomal microarray analysis of fetal tissue, such as amniotic fluid, placenta, or products of conception in the evaluation of intrauterine fetal death or still birth when further cytogenetic analysis is desired because of the test’s increased likelihood of obtaining results and improved detection of causative abnormalities.

In a 2021 Practice Resource Update, American College of Medical Genetics and Genomincs (ACMG) recommended to replace the phrase “expanded carrier screening” with “carrier screening” as expanded is not well defined by professional organizations. The updated guideline also recommends a multi-tiered approach to carrier screening for autosomal recessive and X-linked conditions and suggests the use of non-targeted screening panels for all pregnant individuals or those considering pregnancy.

In a 2024 Technical Standard update on laboratory testing for preconception/prenatal carrier screening, ACMG established the criteria for the design and validation of carrier screening tests, defined the scope and limitations of such tests, established the guidelines for interpreting and reporting test results, and recommended appropriate follow-up testing as applicable.

Targeting at-risk populations has historically been done through identifying ethnic groups that may be isolated or have cultural norms and customs that make them more likely to reproduce with someone of the same ancestry, placing them at a higher risk for transmitting a genetic disorder to their offspring. Marketing and public awareness campaigns by laboratories and advocacy organizations are promoting non-targeted panel screening, arguing that individuals may self- identify with a specific race/ethnicity that is far different from their ancestry defined by genetics, and therefore, would make them unaware of the risk of their fetus being affected by a genetic condition. Non-targeted screening panels have a lack of defined utility in the general population. There are concerns regarding the accuracy of the interpretation of genomic variants, ethical considerations for reproductive decision making, and there are no widely accepted standard multi- gene panels for carrier screening. The offerings of each laboratory may differ in the variants, or number of variants that they include within their panels. It has yet to be determined if the benefits outweigh the costs of non-targeted carrier screening.

References

1. *Alfirevic Z, et al. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev 2017 Sept 04;(3):CD003252.
2. American College of Obstetrics and Gynecologists. ACOG Committee Opinion. Number 682, December 2016, reaffirmed 2020. Microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstetrics & Gynecology 2016 Dec;128(6):e262-e268.
3. *American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol 2007 Dec;110(6):1459-67.
4. American College of Obstetricians and Gynecologists. Committee on Genetics. Carrier screening for genetic conditions. ACOG committee opinion. Number 691. Reaffirmed 2023 [https://www.acog.org/clinical/clinical-guidance/committee- opinion/articles/2017/03/carrier-screening-for-genetic-conditions] accessed 10/01/24.
5. *American College of Medical Genetics. Second trimester maternal serum screening for fetal open neural tube defects and aneuploidy. Policy statement. Genet Med 2009 Nov;11(11):818-21.
6. *American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 799, Preimplantation genetic testing. Obstet Gynecol 2020 Mar;135(3):e133-e137.
7. Bhatt SJ, et al. Pregnancy outcomes following in vitro fertilization frozen embryo transfer with or without preimplantation genetic testing for aneuploidy in women with recurrent pregnancy loss. Human Reprod 2021 Apr;36(8):2339-2344.
8. Capalbo A, et al. Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population. Hum Reprod 2021 May;36(7):2050-2061.
9. *Caughey AB, et al. Chorionic villus sampling compared with amniocentesis and the difference in the rate of pregnancy loss. Obstet Gynecol 2006 Sep;108(3 Pt 1):612-6.
10. De Wert G, et al. The ethics of preconception expanded carrier screening in patients seeking assisted reproduction. Hum Reprod Open 2021 Feb 12;2021(1):hoaa063.
11. *Ethics Committee of the American Society for Reproductive Medicine. Use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions: an Ethics Committee opinion. Fert and Steril 2018 Jun;109(6):989-992.
12. Fesahat F, et al. Preimplantation genetic testing in assisted reproduction technology. J Gynecol Obstet Hum Reprod 2020 May;49(5):101723.
13. *Gregg AR, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics. Genet Med 2021 Jul;23:1793-1806.
14. *Guha, S, et al. Laboratory testing for preconception/prenatal carrier screening: a technical standard of the American college of medical genetics and genomics (ACMG). Genet Med 2024 Jul;26(7):101137.
15. Harris BS, et al. Success rates with preimplantation genetic testing for aneuploidy (PGT-A) in good prognosis patients is dependent on age. Fertility and Sterility 2024 Sep 28: S0015-0282(24)02261-1.
16. Kemper BJ, et al. Preimplantation genetic testing for aneuploidy: a review. Obstet Gynecol Surv 2019 Dec;74(12):727- 737.
17. Khalife D, et al. Review of current guidelines for recurrent pregnancy loss: new strategies for optimal evaluation of women who may be superfertile. Semin Perinatol 2019 Mar;43(2):105-115.
18. *Middleburg KJ, et al. Mental, psychomotor, neurologic, and behavioral outcomes of 2-year-old children born after preimplantation genetic screening: follow-up of a randomized controlled trial. Fertil Steril 2011 Jul;96(1):165-9.
19. *National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. V.1.2025. September 11,2024 [https://www.nccn.org/guidelines/guidelines- detail?category=2&id=1503] accessed 10/01/24.
20. Paulson RJ, Hidden in plain sight: the oversated benefits and underestimated losses of potential
21. implantations associated with advertised PGT-A success rates. Hum Reprod 2020 Mar 27;35(3):490-493.
22. *Pehlivan T, et al. Impact of preimplantation genetic diagnosis on IVF outcome in implantation failure patients. Reprod Biomed Online 2003 Mar;6(2):232-7.
23. *Practice Committee of the American Society of Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012 Nov;98(5):1103-11.
24. *Practice Committee of the American Society of Reproductive Medicine. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril 2018 Mar;109(3):429-436.
25. *Practice Committee of the American Society of Reproductive Medicine. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril 2024 Sep;122(3):421-434.
26. Singer A and Sagi-Dain L. Impact of a national genetic carrier-screening program for reproductive purposes. Acta Obstet Gynecol Scand 2020 Jun;99(6):802-808.
27. Ubaldi FM, et al. Advanced Maternal Age in IVF: still a challenge? The present and the future of its treatment. Front in Endocrin 2019 Feb;10(94):1-12.
28. Van der Schoot V, et al. Preimplantation genetic testing for more than one genetic condition: clinical and ethical considerations and dilemmas. Human Reprod 2019 Jun4;34(6):1146-1154.
29. Vlajkovic T, et al. Day 5 versus day 3 embryo biopsy for preimplantation genetic testing for monogenic/single gene defects. Cochrane Database Syst Rev 2022 Nov 24; 11(11).
30. *Key Article

Coding Section

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare & Medicaid Services (CMS).

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all- inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval

status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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