OMIM Online Mendelian Inheritance in Man⁵⁵

^aAfter rounding values are < 0.02 and ≥ 0.01 (two decimal places).

Table 3. Autosomal recessive genes for screening with carrier frequency < 1/100 to ≥ 1/150.

CFTR Variant Testing

In 2020, the ACMG provided a technical standard for CFTR variant testing. These standards state the following as it pertains to pregnancy:

“During pregnancy, simultaneous testing may be desired depending on gestational age, family and personal history, ethnicity, or patient preferences. Carrier testing may be offered to individuals with a positive family history of CF, in partners of individuals with a positive family history, in partners of CAVD males, to reproductive age women, and to gamete donors. CFTR variant testing can also be performed for prenatal diagnosis using cells obtained for diagnostic cytogenetic testing (i.e., amniocentesis or chorionic villus sampling [CVS]).” 

“As a way to ensure that CFTR variant testing for carrier screening and diagnostic testing purposes remains inclusive, the ACMG recommends either a classification-based reporting approach or a classification-based (targeted) testing approach (which has historically been used for CFTR carrier screening). For those laboratories who wish to continue using a targeted testing approach, the ACMG-23 variant panel remains as the minimum list of CFTR variants that should be included. Laboratories may want to consider adding additional variants to their panel depending on the ethnic composition of their expected test population. However, the minimum list of CFTR variants recommended for pan-ethnic carrier screening has not been increased at this time."

In 2023, the ACMG provided updated recommendations for CFTR carrier screening which includes a new minimum CFTR variant set (increased from 23 to 100 variants). The updated ACMG position statement states the following:

“This new set now supersedes the previous set of 23 CFTR variants recommended by the ACMG. These revised recommendations apply only to carrier screening. They do not apply to CFTR variant testing for diagnosis or newborn screening. All other aspects of the updated 2020 ACMG CFTR technical standards still apply."

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." 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." 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." 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.” This was reaffirmed in 2023.
• 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.” 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."

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.

Paternal and Fetal Genotyping in the Management of Alloimmunization in Pregnancy:³⁹ 

• “Paternal RHD zygosity testing using genotypic analysis is recommended for Rh-D alloimmunization risk assessment. It may be reasonable to defer or discontinue fetal surveillance for anemia in the setting of paternal genotyping that is RHD homozygous negative.”
• “Fetal antigen genotyping is recommended when the paternal genotype is heterozygous or unknown.”
• “Because cfDNA testing possesses performance characteristics that appear comparable with those of molecular testing, while avoiding the rare complications and costs associated with diagnostic genetic testing, it is reasonable to use it as an alternative tool for fetal RHD testing among alloimmunized patients with potentially at-risk pregnancies who decline amniocentesis.”
• “Cell-free DNA for the assessment of selected non–Rh-D red blood cell antigens may be considered for pregnant patients declining amniocentesis, after weighing cost, access, and the encouraging-yet-limited data supporting its use.”

In case of human Rho(D) immune globulin (Rhlg) shortages, ACOG has “prioritization and conservation strategies for consideration.” “Although current ACOG guidance does not recommend routine use of noninvasive prenatal testing (NIPT) to determine fetal Rh(D) status based on cost-effectiveness analyses, the use of NIPT to prioritize use of RhIg and conserve RhIg supply is a reasonable consideration in the practice setting that is experiencing RhIg shortages.” ACOG further states that “Noninvasive fetal red blood cell antigen genotyping utilizing cell-free DNA (cfDNA) isolated from maternal plasma has demonstrated high sensitivity and specificity for detection of fetal Rh(D) antigen status. If cfDNA testing results confirm an Rh(D)-negative fetus, RhIg would not need to be routinely administered in the antepartum period (for bleeding, abortion, pregnancy loss, or at 28 weeks of gestation). Available cfDNA testing options for Rh(D) may vary depending on location and practice setting (eg, companies offering the test; whether the test is offered as a stand-alone or combined with aneuploidy testing; timing of results; insurance coverage) and should be confirmed before implementation.”

Genetic Carrier Screening: Concerning genetic carrier screening, including testing for specific conditions, ACOG recommends (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."
• 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."

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

• “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." 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.

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.” 

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.

British Society for Haematology (BSH)

• The BSH states that, “Invasive testing is not contraindicated if alloimmunisation has occurred. There is a risk of increasing the degree of alloimmunisation, or causing alloimmunisation to new antigens, as a result of the procedure, and this should be discussed with the woman. If the mother is RhD negative and is not already sensitised, anti-D immunoglobulin should be given following the procedure.” The BSH also reiterates that “The use of high- throughput, non-invasive prenatal diagnosis of foetal RHD status was recommended by the National Institute for Health and Care Excellence (NICE) in 2016.”

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, 81252, 81253, 81255, 81257, 81260, 81290, 81329, 81330, 81400, 81401, 81403, 81404, 81405, 81406, 81412, 81443, 81479, 81599, S3844,  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

Grant A, Mohide P. Screening and diagnostic tests in antenatal care. Effectiveness and satisfaction in antenatal care. 1982:22-59.

Lockwood CJ, Magriples U. Prenatal care: Initial assessment. Wolters Kluwer. Updated May 15. https://www.uptodate.com/contents/prenatal-care-initial-assessment

de Jong A, Maya I, van Lith JM. Prenatal screening: current practice, new developments, ethical challenges. Bioethics. 2015;29(1):1-8. doi:10.1111/bioe.12123

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

Miller D. Use of chromosomal microarray in obstetrics. Updated July 31, 2024. https://www.uptodate.com/contents/use-of-chromosomal-microarray-in-obstetrics

LabCorp. Inheritest. https://www.integratedgenetics.com/patients/pre-pregnancy/inheritest

Hoskovec J, Hardisty EE, Talati AN, et al. Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions. Genetics in Medicine. 2023;25(2):100334. doi:10.1016/j.gim.2022.10.014

BillionToOne. UNITY Complete: The New Standard In Prenatal Care. https://www.unityscreen.com/

Calhoun D, Marvin Bahr T. Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management. Updated July 15, 2024. https://www.uptodate.com/contents/alloimmune-hemolytic-disease-of-the-newborn-postnatal-diagnosis-and-management

Moise K. RhD alloimmunization: Prevention in pregnant and postpartum patients. Updated September 17, 2024. https://www.uptodate.com/contents/rhd-alloimmunization-prevention-in-pregnant-and-postpartum-patients

Daniels G, Finning K, Martin P, Summers J. Fetal RhD genotyping: a more efficient use of anti-D immunoglobulin. Transfus Clin Biol. 2007;14(6):568-71. doi:10.1016/j.tracli.2008.03.007

Kent J, Farrell AM, Soothill P. 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. 2014;14:87. doi:10.1186/1471-2393-14-87

Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. Bmj. 2008;336(7648):816-8. doi:10.1136/bmj.39518.463206.25

de Haas M, Thurik FF, van der Ploeg CP, et al. Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. Bmj. Nov 7 2016;355:i5789. doi:10.1136/bmj.i5789

Manfroi S, Calisesi C, Fagiani P, et al. Prenatal non-invasive foetal RHD genotyping: diagnostic accuracy of a test as a guide for appropriate administration of antenatal anti-D immunoprophylaxis. Blood Transfus. 2018;16(6):514-524. doi:10.2450/2018.0270-17

Yesilcinar I, Guvenc G. Counselling and education for prenatal screening and diagnostic tests for pregnant women: Randomized controlled trial. Int J Nurs Pract. 2021;27(5):e13000. doi:10.1111/ijn.13000

Migliorini S, Saccone G, Silvestro F, et al. First-trimester screening based on cell-free DNA vs combined screening: A randomized clinical trial on women's experience. Prenat Diagn. 2020;40(11):1482-1488. doi:10.1002/pd.5800

Biro O, Rigo J, Jr., Nagy B. Noninvasive prenatal testing for congenital heart disease - cell-free nucleic acid and protein biomarkers in maternal blood. J Matern Fetal Neonatal Med. Mar 2020;33(6):1044-1050. doi:10.1080/14767058.2018.1508437

Persico N, Boito S, Ischia B, et al. Cell‐free DNA testing in the maternal blood in high‐risk pregnancies after first‐trimester combined screening. Prenatal Diagnosis. 2016;36(3):232-236.

Dondorp W, de Wert G, Bombard Y, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. European journal of human genetics : EJHG. 2015;23(11):1438-1450. doi:10.1038/ejhg.2015.57

Gil MM, Akolekar R, Quezada MS, Bregant B, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal diagnosis and therapy. 2014;35(3):156-73. doi:10.1159/000358326

Martinez-Payo C, Bada-Bosch I, Martinez-Moya M, Perez-Medina T. Clinical results after the implementation of cell-free fetal DNA detection in maternal plasma. The journal of obstetrics and gynaecology research. 2018;44(8):1369-1376. doi:10.1111/jog.13672

Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. Bjog. 2017;124(1):32-46. doi:10.1111/1471-0528.14050

Clausen FB, Steffensen R, Christiansen M, et al. Routine noninvasive prenatal screening for fetal RHD in plasma of RhD-negative pregnant women-2 years of screening experience from Denmark. Prenat Diagn. 2014;34(10):1000-5. doi:10.1002/pd.4419

Yang H, Llewellyn A, Walker R, et al. High-throughput, non-invasive prenatal testing for fetal rhesus D status in RhD-negative women: a systematic review and meta-analysis. BMC Med. Feb 14 2019;17(1):37. doi:10.1186/s12916-019-1254-4

Darlington M, Carbonne B, Mailloux A, et al. Effectiveness and costs of non-invasive foetal RHD genotyping in rhesus-D negative mothers: a French multicentric two-arm study of 850 women. BMC Pregnancy Childbirth. 2018;18(1):496. doi:10.1186/s12884-018-2114-5

Runkel B, Bein G, Sieben W, Sow D, Polus S, Fleer D. Targeted antenatal anti-D prophylaxis for RhD-negative pregnant women: a systematic review. BMC Pregnancy Childbirth. 2020;20(1):83. doi:10.1186/s12884-020-2742-4

Westin ER, Tsao DS, Atay O, et al. Validation of single‐gene noninvasive prenatal testing for sickle cell disease. American Journal of Hematology. 2022;97(7)doi:10.1002/ajh.26570

Zhu X, Chen M, Wang H, et al. Clinical utility of expanded noninvasive prenatal screening and chromosomal microarray analysis in high risk pregnancies. Ultrasound Obstet Gynecol. 2020;doi:10.1002/uog.22021

Zhang H, He J, Teng Y, et al. Non-invasive prenatal testing for dominant single-gene disorders using targeted next-generation sequencing. Qjm. Feb 21 2025;doi:10.1093/qjmed/hcaf017

Gregg AR, Aarabi M, Klugman S, 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 (ACMG). Genet Med. 2021;23(10):1793-1806. doi:10.1038/s41436-021-01203-z

Deignan JL, Astbury C, Cutting GR, et al. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2020/08/01/ 2020;22(8):1288-1295. doi:10.1038/s41436-020-0822-5

Deignan JL, Gregg AR, Grody WW, et al. Updated recommendations for CFTR carrier screening: A position statement of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2023;25(8):100867. doi:10.1016/j.gim.2023.100867

ACOG. Committee Opinion No. 690: Carrier Screening in the Age of Genomic Medicine. Obstetrics and gynecology. Mar 2017;129(3):e35-e40. doi:10.1097/aog.0000000000001951

ACOG. Consumer Testing for Disease Risk: ACOG Committee Opinion, Number 816. Obstetrics and gynecology. Jan 1 2021;137(1):e1-e6. doi:10.1097/AOG.0000000000004200

ACOG. ACOG Committee Opinion No. 727: Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated With Cancer. Obstetrics and gynecology. Jan 2018;131(1):e31-e34. doi:10.1097/aog.0000000000002457

ACOG. Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. Obstetrics and gynecology. May 2016;127(5):e108-e122. doi:10.1097/AOG.0000000000001405

ACOG. ACOG Clinical Practice Update: Paternal and Fetal Genotyping in the Management of Alloimmunization in Pregnancy. https://journals.lww.com/greenjournal/abstract/2024/08000/acog_clinical_practice_update__paternal_and_fetal.34.aspx

ACOG. Rho(D) Immune Globulin Shortages. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2024/03/rhod-immune-globulin-shortages

ACOG. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstetrics and gynecology. Mar 2017;129(3):e41-e55. doi:10.1097/aog.0000000000001952

ISPD. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38(1):6-9. doi:10.1002/pd.5195

Palomaki GE, Chiu RWK, Pertile MD, et al. International Society for Prenatal Diagnosis Position Statement: cell free (cf)DNA screening for Down syndrome in multiple pregnancies. Prenat Diagn. 2021;41(10):1222-1232. doi:10.1002/pd.5832

Sandler SG, Flegel WA, Westhoff CM, et al. 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. 2015;55(3):680-9. doi:10.1111/trf.12941

Regan F, Veale K, Robinson F, et al. Guideline for the investigation and management of red cell antibodies in pregnancy: A British Society for Haematology guideline. Transfus Med. Feb 2025;35(1):3-23. doi:10.1111/tme.13098

Medical Director review 7/2022

Medical Director review 7/2023

Medical Director review 7/2024

Medical Director review 7/2025

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)

10/15/25   Reviewed with Avalon Q3 CAB 2025. Updated description, related policies, policy guidelines, and references. Updated Billing/Coding section to add 81252, 81253, and S3844. Medical Director review 7/2025. (tt)