American College of Obstetricians and Gynecologists (ACOG)

ACOG has several practice guidelines related to prenatal care as well as both pre-conception and prenatal testing. ACOG recommendations and guidelines include the following:

Genetic Testing and Genetic Counseling: Concerning genetic testing and genetic counseling, ACOG recommends: 

• “The routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published” (ACOG, 2016a). This was reaffirmed in 2023.
• Chromosomal microarray analysis (CMA) is recommended for patients with a fetus with at least one major structure abnormality identified via ultrasound. CMA can be considered for all pregnant individuals who undergo prenatal diagnostic testing; however, “In a patient with a structurally normal fetus who is undergoing invasive prenatal diagnostic testing, either fetal karyotyping or a chromosomal microarray analysis can be performed. Chromosomal microarray analysis of fetal tissue (ie, amniotic fluid, placenta, or products of conception) is recommended in the evaluation of intrauterine fetal death or stillbirth when further cytogenetic analysis is desired because of the test’s increased likelihood of obtaining results and improved detection of causative abnormalities” (ACOG, 2016a). This was reaffirmed in 2023.
• “All patients who are considering pregnancy or are already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for cystic fibrosis and spinal muscular atrophy, as well as a complete blood count and screening for thalassemias and hemoglobinopathies. Fragile X premutation carrier screening is recommended for [individuals] with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome, or [individuals] with a personal history of ovarian insufficiency. Additional screening also may be indicated based on family history or specific ethnicity” (ACOG, 2017a). This was reaffirmed in 2023. 
• “The American College of Obstetricians and Gynecologists discourages direct-to-consumer genetic testing without appropriate counseling. . . Patients may present after direct-to-consumer testing already has been performed, and clinicians should be prepared to review these results or refer to a health care professional with the appropriate knowledge, training, and experience in interpreting test results. . . Given the insufficient data to support the use of single nucleotide polymorphisms (SNP) testing for medical purposes, SNP testing to provide individual risk assessment for a variety of diseases or to tailor drug therapy outside of an institutional review board-approved research protocol is not recommended. The American College of Obstetricians and Gynecologists recommends that the use of these technologies be viewed as investigational at this time” (ACOG, 2021).
• ACOG notes that “Cascade testing has been shown to be cost effective in part because testing for specific mutations (e.g., those identified in the affected relative) is less expensive than whole-gene sequencing” (ACOG, 2018). This was reaffirmed in 2022. 

Prenatal Diagnostic Testing for Genetic Disorders: Concerning prenatal diagnostic testing for genetic disorders, ACOG has published the following recommendations:

• “An abnormal FISH result should not be considered diagnostic. Therefore, clinical decision making based on information from FISH should include at least one of the following additional results: confirmatory traditional metaphase chromosome analysis or chromosomal microarray, or consistent clinical information (such as abnormal ultrasonographic findings or a positive screening test result for Down syndrome or trisomy 18).”
• “All pregnant women should be offered prenatal assessment for aneuploidy by screening or diagnostic testing regardless of maternal age or other risk factors.”
• “Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient’s risks, reproductive goals and preferences.”
• “Genetic testing should be discussed as early as possible in pregnancy, ideally at the first obstetric visit, so that first-trimester options are available” (ACOG, 2016b).

Prevention of Rh D Alloimmunization: Concerning the prevention of Rh D alloimmunization, ACOG has published the guidelines supporting the administration of anti-D immune globulin to individuals in various scenarios. However, these guidelines do not mention the use of cell-free fetal DNA for fetal RHD testing to determine if anti-D immune globulin is needed (ACOG, 2017c).

Genetic Carrier Screening: Concerning genetic carrier screening, including testing for specific conditions, ACOG recommends [(ACOG, 2017a, 2017b) reaffirmed 2023]:

• “Carrier screening and counseling ideally should be performed before pregnancy.” 
• “If an individual is found to be a carrier for a specific condition, the individual’s reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. Concurrent screening of the patient and her partner is suggested if there are time constraints for decisions about prenatal diagnostic evaluation.”
• “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. Because of the rapid evolution of genetic testing, additional mutations may be included in newer screening panels. The decision to rescreen a patient should be undertaken only with the guidance of a genetics professional who can best assess the incremental benefit of repeat testing for additional mutations.”
• “Prenatal carrier screening does not replace newborn screening, nor does newborn screening replace the potential value of prenatal carrier screening.”
• “The cost of carrier screening for an individual condition may be higher than the cost of testing through commercially available expanded carrier screening panels. When selecting a carrier screening approach, the cost of each option to the patient and the health care system should be considered.”
• “Screening for spinal muscular atrophy should be offered to all [individuals] who are considering pregnancy or are currently pregnant. In patients with a family history of spinal muscular atrophy, molecular testing reports of the affected individual and carrier testing of the related parent should be reviewed, if possible, before testing. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner.”
• “Cystic fibrosis carrier screening should be offered to all [individuals] who are considering pregnancy or are currently pregnant. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.”
• “A complete blood count with red blood cell indices should be performed in all [individuals] who are currently pregnant to assess not only their risk of anemia but also to allow assessment for risk of a hemoglobinopathy. Ideally, this testing also should be offered to [individuals] before pregnancy. A hemoglobin electrophoresis should be performed in addition to a complete blood count if there is suspicion of hemoglobinopathy based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent). If red blood cell indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume, hemoglobin electrophoresis also should be performed.”
• “Fragile X premutation carrier screening is recommended for [individuals] 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.”
• “If a [individual] has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation.”
• “All identified individuals with intermediate results and carriers of a fragile X premutation or full mutation should be provided follow-up genetic counseling to discuss the risk to their offspring of inheriting an expanded full-mutation fragile X allele and to discuss fragile X-associated disorders (premature ovarian insufficiency and fragile X tremor/ataxia syndrome).”
• “Prenatal diagnostic testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation.”
• “DNA-based molecular analysis (e.g., Southern blot analysis and polymerase chain reaction) is the preferred method of diagnosis of fragile X syndrome and of determining FMR1 triplet repeat number (e.g., premutations). In rare cases, the size of the triplet repeat and the methylation status do not correlate, which makes it difficult to predict the clinical phenotype. In cases of this discordance, the patient should be referred to a genetics professional.”
• “When only one partner is of Ashkenazi Jewish descent, that individual should be offered screening first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals are unknown for most of these disorders, except for Tay–Sachs disease and cystic fibrosis. Therefore, it is difficult to accurately predict the couple’s risk of having a child with the disorder.”
• “Screening for Tay–Sachs disease should be offered when considering pregnancy or during pregnancy if either member of a couple is of Ashkenazi Jewish, French Canadian, or Cajun descent. Those with a family history consistent with Tay–Sachs disease also should be offered screening. When one member of a couple is at high risk (i.e., of Ashkenazi Jewish, French Canadian, or Cajun descent or has a family history consistent with Tay–Sachs disease) but the other partner is not, the high-risk partner should be offered screening. If the high-risk partner is found to be a carrier, the other partner also should be offered screening. Enzyme testing in pregnant [individuals] and [individuals] taking oral contraceptives should be performed using leukocyte testing because serum testing is associated with an increased false-positive rate in these populations. If Tay–Sachs disease screening is performed as part of pan-ethnic expanded carrier screening, it is important to recognize the limitations of the mutations screened in detecting carriers in the general population. In the presence of a family history of Tay–Sachs disease, expanded carrier screening panels are not the best approach to screening unless the familial mutation is included on the panel” (ACOG, 2017b).
• Regarding expanded carrier screening panels, ACOG recommends that “the disorders selected for inclusion should meet several of the following consensus-determined criteria: have a carrier frequency of 1 in 100 or greater, have a well-defined phenotype, have a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life.” ACOG further states that “screened conditions should be able to be diagnosed prenatally and may afford opportunities for antenatal intervention to improve perinatal outcomes, changes to delivery management to optimize newborn and infant outcomes, and education of the parents about special care needs after birth” (ACOG, 2017a).

Carrier Screening in the Age of Genomic Medicine: Concerning carrier screening in the age of genomic medicine, the ACOG has published the following guidelines (ACOG, 2017a):

• “Ethnic-specific, pan-ethnic and expanded carrier screening are acceptable strategies for prepregnancy and prenatal carrier screening
• If a patient requests a screening strategy other than the one used by the obstetrician-gynecologist or other health care provider, the requested test should be made available to her after counseling on its limitations, benefits, and alternatives.
• All patients who are considering pregnancy or already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for cystic fibrosis and spinal muscular atrophy, as well as a complete blood count and screening for thalassemias and hemoglobinopathies. Fragile X premutation carrier screening is also recommended for [individuals] with a family history of fragile x-related disorders or intellectual disability suggestive of fragile X syndrome, or [individuals] with a personal history of ovarian insufficiency. Additional screening also may be indicated based on family history or specific ethnicity.
• If a [individual] is found to be a carrier for a specific condition, her reproductive partner should be offered screening to provide accurate genetic counseling for the couple with regard to the risk of having an affected child. Additional genetic counseling should be provided to discuss the specific condition, residual risk, and options for prenatal testing.
• Individuals with a family history of a genetic disorder may benefit from the identification of the specific familial mutation or mutations rather than carrier screening. Knowledge of the specific familial mutation may allow for more specific and rapid prenatal diagnosis.
• Given the multitude of conditions that can be included in expanded carrier screening panels, the disorders selected for inclusion should meet several of the following consensus-determined criteria: have a carrier frequency of 1 in 100 or greater, have a well-defined phenotype, have a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life. Additionally, screened conditions should be able to be diagnosed prenatally and may afford opportunities for antenatal intervention to improve perinatal outcomes, changes to delivery management to optimize newborn and infant outcomes, and education of the parents about special care needs after birth.
• Carrier screening panels should not include conditions primarily associated with a disease of adult onset” (ACOG, 2017a). This guideline was reaffirmed in 2023.

International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) 

The ISPD, SMFM and PQF published the following guidelines on the use of genome-wide sequencing for fetal diagnosis:

• The use of diagnostic sequencing is currently being introduced for evaluation of fetuses for whom standard diagnostic genetic testing, such as chromosomal microarray analysis (CMA), has already been performed and is uninformative, is offered concurrently according to accepted practice guidelines, or for whom expert genetic opinion determines that standard genetic testing is less optimal than sequencing for the presenting fetal phenotype. 
• The routine use of prenatal sequencing as a diagnostic test cannot currently be supported due to insufficient validation data and knowledge about its benefits and pitfalls (ISPD, 2018).

In addition to the joint position statement released in 2018, the IPSD released a guideline in 2020 on the use of cfDNA screening for trisomies in multiple pregnancies:

• “The use of first trimester cfDNA screening for the common autosomal trisomies is appropriate for twin pregnancies due to sufficient evidence showing high detection and low false positive rates with high predictive values. Moderate.” 
• “It is preferable for laboratories performing cfDNA testing in multi-fetal pregnancies to take evidence of zygosity into consideration (eg, chorionicity, sex of the fetuses, embryo transfer history) for the interpretation of both test results and fetal fractions. Moderate.” 
• “Screening options for triplet pregnancies are lacking and cfDNA may be a potential option. However, diagnostic testing should always be offered and the limitations of screening tests stressed. Low” (Palomaki et al., 2021).

College of American Pathologists (CAP) Transfusion Medicine Resource Committee (TMRC) Work Group

The following recommendations were given by the CAP TMRC Work Group:

• The Work Group recommends that RHD genotyping be performed whenever a discordant RhD typing result and/or a serological weak D phenotype is detected in patients, including pregnant individuals, newborns, and potential transfusion recipients. It is anticipated that the immediate benefit will be fewer unnecessary injections of RhIG and increased availability of RhD-negative RBCs for transfusion.
• Other than RHD genotypes weak D type 1, 2, or 3, the Work Group recommends that individuals with a serological weak D phenotype receive conventional prophylaxis with RhIG, including postpartum RhIG if the newborn is RhD-positive or has a serological weak D phenotype (Sandler et al., 2015).

State and Federal Regulations, as applicable

The FDA has approved many tests for conditions that can be included in a prenatal screening, such as HSV, chlamydia, gonorrhea, syphilis, and diabetes. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81171, 81172, 81200, 81209, 81241, 81242, 81243, 81244, 81251, 81255, 81257,81260, 81290, 81329, 81330, 81400, 81401, 81403, 81404, 81405, 81406, 81412, 81443, 81479, 81599,  S3845, S3846, S3849, 0400U, 0449U, 0488U, 0489U, 0494U, and 0536U

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

ACOG. (2016a). Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol, 128(6), e262-e268. https://doi.org/10.1097/aog.0000000000001817

ACOG. (2016b). Prenatal Diagnostic Testing for Genetic Disorders. https://s3.amazonaws.com/cdn.smfm.org/publications/223/download-f5260f3bc6686c15e4780f8100c74448.pdf

ACOG. (2017a). Committee Opinion No. 690: Carrier Screening in the Age of Genomic Medicine. Obstet Gynecol, 129(3), e35-e40. https://doi.org/10.1097/aog.0000000000001951

ACOG. (2017b). Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol, 129(3), e41-e55. https://doi.org/10.1097/aog.0000000000001952

ACOG. (2017c). Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. https://journals.lww.com/greenjournal/fulltext/2017/08000/Practice_Bulletin_No__181__Prevention_of_Rh_D.54.aspx

ACOG. (2018). ACOG Committee Opinion No. 727: Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated With Cancer. Obstet Gynecol, 131(1), e31-e34. https://doi.org/10.1097/aog.0000000000002457

ACOG. (2021). Consumer Testing for Disease Risk: ACOG Committee Opinion, Number 816. Obstet Gynecol, 137(1), e1-e6. https://doi.org/10.1097/AOG.0000000000004200

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Gregg, A. R., Aarabi, M., Klugman, S., Leach, N. T., Bashford, M. T., Goldwaser, T., Chen, E., Sparks, T. N., Reddi, H. V., Rajkovic, A., Dungan, J. S., Practice, A. P., & Guidelines, C. (2021). Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 23(10), 1793-1806. https://doi.org/10.1038/s41436-021-01203-z

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Kent, J., Farrell, A. M., & Soothill, P. (2014). Routine administration of Anti-D: the ethical case for offering pregnant women fetal RHD genotyping and a review of policy and practice. BMC Pregnancy Childbirth, 14, 87. https://doi.org/10.1186/1471-2393-14-87

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Sandler, S. G., Flegel, W. A., Westhoff, C. M., Denomme, G. A., Delaney, M., Keller, M. A., Johnson, S. T., Katz, L., Queenan, J. T., Vassallo, R. R., & Simon, C. D. (2015). It's time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group. Transfusion, 55(3), 680-689. https://doi.org/10.1111/trf.12941

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Zhu, X., Chen, M., Wang, H., Guo, Y., Chau, M. H. K., Yan, H., Cao, Y., Kwok, Y. K. Y., Chen, J., Hui, A. S. Y., Zhang, R., Meng, Z., Zhu, Y., Leung, T. Y., Xiong, L., Kong, X., & Choy, K. W. (2020). Clinical utility of expanded noninvasive prenatal screening and chromosomal microarray analysis in high risk pregnancies. Ultrasound Obstet Gynecol. https://doi.org/10.1002/uog.22021

Medical Director review 7/2022

Medical Director review 7/2023

Medical Director review 7/2024

Policy Implementation/Update Information

9/13/22 New policy developed. BCBSNC will provide coverage for Prenatal Screening (genetic) when the medical criteria and guidelines outlined in the policy are met. Medical Director review 7/2022. Notification give 9/13/2022 for effective date 10/18/2022. (tt)

11/1/22 Policy title updated to include “AHS-M2179” to align with Avalon. (tt)

6/30/23 Added CPT code 0400U to Billing/Coding section, effective 7/1/2023. (tt)

8/15/23 Reviewed with Avalon Q2 CAB 2023. Updated description, policy guidelines, and references. Coverage of carrier screening expanded to include all of Tier 1/2/3 screening as recommended by ACMG. Medical Director review 7/2023. (tt)

9/4/24 Reviewed with Avalon Q2 CAB 2024. Updated description, related policies, policy guidelines, and references. When covered #3 updated for clarification that screening in the reproductive partner is restricted to the genes for which their partner tested positive by carrier screening, not broad screening for themselves. When covered #5 updated for clarification that fetal testing must be a form of testing, not a form of screening (e.g., cfDNA screening), from an amnio or CVS sample. Added “Note 2: For 2 or more gene tests being run on the same platform, please refer to AHS-R2162 Reimbursement Policy” under when covered section. Added the following statement to when not covered: “Reimbursement is not allowed for the use of non-invasive prenatal screening (NIPS) to screen for single-gene mutations (i.e., autosomal recessive, autosomal dominant, X-linked) in the fetus." Added 0449U, 81479, 81599 to Billing/Coding section. Medical Director review 7/2024. Notification given 9/4/2024 for effective date 11/13/2024. (tt)

12/17/24 Added PLA codes 0488U, 0489U, and 0494U to Billing/Coding section. (tt)

4/1/25 Updated Billing/Coding section to add 0536U, effective 4/1/2025. (tt)