Oscar Prenatal Testing (CG043) Form

The Plan

Members who are pregnant may be eligible for prenatal testing to provide information about the health of both the mother and the baby. Prenatal testing can be performed invasively or noninvasively to look for a variety of birth defects and genetic conditions.

Invasive testing includes several more involved procedures such as directly sampling the fluid or tissue surrounding the baby. Non-invasive testing is performed with simple blood tests. Medical necessity for expanded carrier screenings may be limited to risk-based conditions.

These tests can be performed at different stages of the pregnancy depending on the conditions being tested. Screening or diagnostic testing for fetal genetic disorders may be appropriate, regardless of maternal age. Additionally, high risk women, such as those over 35 years of age or with certain medical conditions, are eligible for more advanced testing. Testing must be performed by an in-network provider when available.

This guideline provides medical necessity criteria for prenatal tests and procedures. For a list of tests that includes, but not limited to services considered experimental or investigational, please refer to the Plan Clinical Guideline: Experimental or Investigational (Unproven) Services, Products, Drugs, and Biologicals (CG012).

Definitions

• Invasive Prenatal Testing includes procedures such as amniocentesis and chorionic villus sampling, where the tissue or fluid surrounding the baby is directly sampled.
• Noninvasive Prenatal Testing (NIPT) or Noninvasive Prenatal Screening (NIPS) is a test where a small amount of the mother's blood is drawn to look for fragments of fetal genetic material called cell-free DNA. These small fragments can be used to look for fetal trisomy syndromes and determine the sex of the baby. NIPT can be performed as early as the first trimester (e.g.,10 weeks of gestation). NIPT to screen for trisomy syndromes (trisomy 13, 18, and 21) is becoming more mainstream in community clinical practice but should be followed by a diagnostic test (e.g., chorionic villus sampling or amniocentesis) when making decisions to continue or terminate a pregnancy.
• Nuchal Translucency is a procedure where ultrasound is used to determine the fluid in the neck of the growing baby to determine risk of various conditions such as trisomy 21 or cardiac problems.
• Carrier Screening refers to the genetic testing of certain rare, inheritable conditions such as cystic fibrosis or spinal muscular atrophy. These conditions are usually inherited in an autosomal recessive fashion, meaning, both parents need to have the mutation in order for the baby to be at risk.
• Expanded Carrier Screening refers to genetic screening for multiple disorders instead of screening targeted for at-risk disorders.
• Trisomy is the genetic condition of having an extra chromosome. Where the normal human genome has 23 pairs of chromosomes, errors in reproductive division to create the egg or sperm can result in an extra chromosome being included. The most common trisomies are trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome).
• Aneuploidy is a broad term used to define the presence of an abnormal number of chromosomes. This can include trisomy syndromes, or conditions such as Turner's syndrome where there is a missing chromosome (sex-chromosome aneuploidy)

Clinical Indications

The Plan considers genetic testing medically necessary to establish a molecular diagnosis of an inheritable disease or genetic disorder when ALL of the following are met:

1. The test is FDA-approved or if without FDA approval, it has been evaluated to be clinically beneficial supported by strong clinical evidence (e.g., ACOG, ACMG, Hayes, UpToDate); and
2. The member displays clinical features, or is at direct risk of inheriting the mutation in question (pre-symptomatic); and
3. The result of the test will directly impact the treatment being delivered to the member; and

4. After history, physical examination, pedigree analysis, genetic counseling, and completion of conventional diagnostic studies, a definitive diagnosis remains uncertain; and
5. Testing is accompanied by genetic counseling and documented by a licensed genetic counselor, obstetrician, or maternal-fetal medicine specialist. (Please note: In April 2022, the FDA issued a Safety Communication for patients and providers that genetic non-invasive prenatal screening tests may have false results and most laboratory developed tests are offered on market without FDA review. Therefore, members should discuss the risks and benefits with providers and receive genetic counseling.)

State Law Conflicts

For any provision of this policy that directly conflicts with or is prohibited by state law, the provisions of the state law will apply instead of the provisions of this policy. This means that in instances where state regulations diverge from or directly oppose the Prenatal Testing (CG043) Medical Necessity Criteria for Authorization or requirements, the policy's criteria will not apply.

Non-Invasive Prenatal Cell-Free DNA testing

The Plan considers non-invasive prenatal cell-free DNA testing medically necessary when general criteria above and ALL of the following criteria are met:

• The test is used to screen for fetal sex chromosome aneuploidy, trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) or trisomy 13 (Patau syndrome); and
• The member has a confirmed single or twin pregnancy; and
• The member has not previously had NIPT for this pregnancy; and
• The NIPT test is being performed at > 10 weeks gestation.

Standard CFTR (cystic fibrosis transmembrane conductance regulator) Mutation Panel

The Plan considers carrier screening for cystic fibrosis with the ACMG (American College of Medical Genetics) standard CFTR (cystic fibrosis transmembrane conductance regulator) mutation panel medically necessary when general criteria are met and ANY of the following criteria are met:

1. Couples seeking prenatal care; or
2. Couples planning a pregnancy; or
3. Members with a family history of cystic fibrosis; or
4. Members with a 1st degree relative identified as a cystic fibrosis carrier; or
5. Members with a partner who has cystic fibrosis or is a cystic fibrosis carrier; or
6. When the newborn screen is positive for CF and the sweat chloride test is inconclusive, intermediate or cannot be performed.

Factor V Leiden Testing

The Plan considers factor V Leiden genetic testing in pregnant members or those planning pregnancy medically necessary when general criteria and ALL of the following criteria are met:

1. Abnormal activated protein C (APC) resistance assay test (unless member is receiving anticoagulation); and
2. One of the following situations are met:
   • Venous thromboembolism (VTE) during the current or past pregnancy, or in the 6 weeks following a prior pregnancy; or
   • First degree blood relative with history of high-risk thrombophilia (e.g. antithrombin deficiency, factor V leiden mutation, or prothrombin G20210A mutation); or
   • First-degree blood relative with history of venous thromboembolism prior the age of 50 years old; or
   • Personal history of unprovoked VTE; or
   • Personal history of VTE associated with use of oral contraceptives or hormone therapy

Prothrombin G20210A Thrombophilia (F2 Gene) Testing

The Plan considers prothrombin G20210A thrombophilia (F2 Gene) testing in pregnant members or those planning pregnancy medically necessary when general criteria and ONE of the following criteria are met:

1. Venous thromboembolism (VTE) during the current or past pregnancy, or in the 6 weeks following a prior pregnancy; or
2. First degree blood relative with history of high-risk thrombophilia (e.g. antithrombin deficiency, factor V leiden mutation, or prothrombin G20210A mutation); or
3. First-degree blood relative with history of venous thromboembolism prior the age of 50 years old; or
4. Personal history of unprovoked VTE;

Personal history of VTE associated with use of oral contraceptives or hormone therapy

Hemoglobinopathy and Thalassemia Testing

The Plan considers genetic testing for hemoglobinopathies and thalassemias (includes, but not limited to: Sickle Cell Anemia [HBB Gene], Alpha Thalassemia [HBA1/HBA2 Genes] and Beta Thalassemia [HBB Gene]) for couples planning pregnancy or seeking prenatal care medically necessary when general criteria and ONE of the following criteria are met:

1. Family history of a hemoglobinopathy; or
2. Family member who is affected or is a carrier with a known mutation; or
3. Suspected hemoglobinopathy based on results of a complete blood count (CBC) and hemoglobin analysis, such as low mean corpuscular hemoglobin or mean corpuscular volume; or
4. African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent

Spinal Muscular Atrophy Testing (SMN1 and SMN2)

The Plan considers spinal muscular atrophy genetic testing (SMN1 and SMN2) medically necessary when general criteria and ONE of the following criteria is met:

1. Carrier screening for couples seeking prenatal care or planning pregnancy; or
2. In the fetus or as a pre-implantation test when both parents are known carriers of the mutation

Fragile X Testing (FMRI gene)

The Plan considers fragile X testing (FMRI gene) in pregnant members or those planning pregnancy medically necessary when general criteria and ONE of the following criteria are met:

1. A family history of fragile X syndrome, or
2. A family history of unexplained developmental delay/intellectual disability, autism or primary ovarian insufficiency (POI); or
3. Fetuses of known carrier mothers

Tay-Sachs Disease Testing (HEXA gene)

The Plan considers Tay-Sachs disease testing (HEXA gene) in pregnant members or those planning pregnancy medically necessary when general criteria and ONE of the following criteria are met:

1. The member has an abnormal or inconclusive beta-hexosaminidase A enzyme activity; or
2. The member has an affected or carrier family member in whom a mutation has been identified; or
3. The member or member's partner is of Ashkenazi Jewish, French Canadian, or Cajun descent; or
4. The member or member's partner is affected with or carrier of Tay-Sachs disease

Down Syndrome Testing

The Plan considers the following non-invasive testing options for Down syndrome in pregnant women wishing to undergo testing that have been adequately counseled medically necessary when general criteria are met:

• First trimester combined test, consisting of the following tests, to be used when earlier identification of aneuploidy is desired:
  • Nuchal translucency and
  • PAPP-A and beta-HCG
• Other first trimester tests: Non-Invasive Prenatal Cell-Free DNA testing to support decision-making. Not to be used concurrently with the first trimester combined test, unless high risk.
• When nuchal translucency is not available or the results are indeterminate, serum analyte combined test consisting of the following is warranted:
  • First trimester PAPP-A and beta-HCG and
  • Second trimester quadruple screen
• Second trimester quadruple screen, consisting of the following biomarkers:
  • Dimeric inhibin A and
  • Human chorionic gonadotropin (hCG) and
  • Maternal serum alpha-fetoprotein (MSAFP) and
  • Unconjugated estriol
• Full integrated testing, as defined by combination of the following:
  • First trimester combined test and
  • Second trimester quadruple screen
• Stepwise sequential testing, as defined by:
  • Initial first trimester combined test, followed by risk stratification, and if necessary, second trimester quadruple screen

In addition to the above carrier screens and genetic tests, the Plan considers genetic testing of the diseases listed in Table 1 medically necessary when general criteria and ANY of the following criteria are met:

1. Genetic testing for a known familial variant mutation when it has been identified in the member, the member’s partner, or a blood relative; or
2. Targeted mutation analysis when ONE of the following criteria is met:

2. The member or reproductive partner is a known carrier of a disease-causing recessively inherited mutation; or
3. A disease-causing recessively inherited mutation has been identified in a blood relative and the relative has not had testing or is unavailable for genetic testing; or

3. Gene sequencing and/or gene duplication/deletion analysis when ONE of the following criteria is met:
   • The member meets criteria for target mutation analysis above; or
   • Targeted mutation analysis is not available or was previously negative

Table 1: Genetic diseases

Expanded Carrier Screening Panels

Expanded carrier screening may be considered medically necessary when general criteria are met and the indication and testing performed are consistent with the criteria set forth by the American Congress of Obstetricians and Gynecologists Committee on Genetics:

• The carrier frequency is greater than 1 in 100; and
• The phenotype is well-defined; and
• The condition will have a detrimental effect on quality of life; and
• The condition will cause cognitive and/or physical impairment; and
• The condition may require medical or surgical intervention; and
• The condition can be diagnosed prenatally; and
• The condition may be amenable to antenatal intervention to improve perinatal outcomes and may change delivery management.
• The condition is associated with early onset in life and not adult onset.

Chorionic Villus Sampling or Amniocentesis

For women with a major fetal structural abnormality detected on ultrasound examination and when MCG criteria are met, chorionic villus sampling or amniocentesis with chromosomal microassay are medically necessary.

Experimental or Investigational / Not Medically Necessary

• Non-Invasive Prenatal Cell-Free DNA testing for multiple gestation pregnancies with ≥ 3 fetuses.
  • Rationale:The use of NIPT cell-free DNA testing in multiple gestations more than twins is not endorsed by the ACOG, ACMG, SMFM, or other professional societies due to lack of testing in this population and concerns over a higher rate of false negatives given the potential for variable amounts of cell-free DNA from each fetus.
• Vanishing twin syndrome or demised twin
  • Rationale:There are increased rates of false positives in cases of vanishing or demised twin in cases where the twin was aneuploid.
• Screening for trisomy of chromosome: 7, 9, 16, or 22
  • Rationale:Evaluation for rare trisomies has not been fully explored in the literature, therefore the diagnostic utility of cell-free DNA testing in this setting has not yet been adopted by expert consensus guidelines.
• Screening for microdeletions
  • cfDNA screening tests for microdeletions have not been validated clinically and are not recommended at this time (ACOG, 2016).
• Whole genome NIPT
  • Rationale:The outcomes and clinical utility of whole genome sequencing have not been validated in the scientific literature. Further research is required prior to guide clinical use.
• When used to determine the etiology of recurrent miscarriage
  • Rationale:The outcomes and clinical utility of cell-free DNA testing have not been validated in the scientific literature for evaluation of recurrent miscarriage.

Further research is required prior to guiding clinical use.

• When used to determine fetal sex
  • Rationale: While NIPT has demonstrated the potential for determining fetal sex, the clinical outcomes and medical necessity of this indication have not been validated in the literature and using NIPT to determine fetal sex has not received formal guidance from the expert societies.
• Fetal rhesus D (RhD) genotyping
  • Rationale: NIPT has seen some adoption across Europe in prenatal determination of Rhesus D genotyping, however, has not yet demonstrated improvement in clinical outcomes across large, validated studies. The ACOG and SMFM currently do not mention rhesus D genotyping as an indication for NIPT cfDNA testing.
• Cystic hygroma
  • Rationale: Cystic hygroma is considered a high-risk condition for fetal aneuploidy and thus direct consideration for invasive testing should be the next step. ACOG guidelines for cell-free DNA testing state, "If a fetal structural anomaly is identified on ultrasound examination, diagnostic testing should be offered rather than cell-free DNA screening".

Non-Invasive Down Syndrome Screening

The following tests and biomarkers for the non-invasive screening for Down syndrome and other prenatal conditions are considered experimental, investigational, or unproven and thus not medically necessary unless performed as:

• Second trimester screening with:
  • Beta subunit of hCG
  • Human placental lactogen
  • Pregnancy-associated plasma protein A (PAPP-A)
  • Urinary beta-core
  • Rationale: The clinical efficacy of diagnosing trisomy syndromes with these biomarkers has been evaluated primarily for first trimester pregnancies and has not been established for use in the second trimester and may be inferior to first trimester use.
• A Disintegrin Metalloprotease 12 (ADAM12)
  • Rationale: Laigaard et al (2007) looked at the use of ADAM12 as a first trimester screen for Down syndrome and found reduced levels of the biomarker, however stated that further research was needed to define its role in the screening process. A second study by Christiansen et al (2007) came to the same conclusions for ADAM12 use in the second trimester. ACOG and other societies do not currently mention the use of this biomarker.
• Placental protein 13 (PP13)
  • Rationale: Koster et al (2009) looked at the use of PP13 as a first trimester screen for Down syndrome and other common trisomies. They found non-significant differences in Down syndrome and variable decreases of the biomarker in other trisomies, and concluded that PP13 was NOT a good marker for Down Syndrome screening.
• First-trimester NT measurement alone (without first-trimester serum analyte testing) in the absence of fetal cystic hygroma in singleton pregnancies
  • Rationale: Nuchal translucency testing alone is not recommended by any of the expert consensus guidelines from ACOG or other specialty-specific societies. Research has shown that adding biomarker testing to the ultrasound decreases the rate of fetal karyotyping required and improves the predictive value.
• First-trimester serum analyte testing (hCG* and PAPP-A) alone without NT measurement
  • Rationale: First trimester biomarker testing alone is not recommended by any of the expert consensus guidelines from ACOG or other specialty-specific societies. The FASTER and SURUSS studies have shown that combining first trimester screening with nuchal translucency or with second trimester quadruple screen increases the detection rate and decreases false positives.
• First-trimester ultrasound assessment of the nasal bone
  • Rationale: A large study of 1027 patients by Orlandi et al (2003) looked at ultrasound of the nasal bone as a marker for Down syndrome.

• First-trimester ultrasound assessment of the nasal bone
  • Rationale: While they noted that its inclusion in first trimester screening might have some utility, they concluded that "Large datasets are needed to confirm whether the measurement of nasal bone length provides additional benefits beyond the assessment of the presence or absence of the nasal bone."
• Any other biomarker not defined above, including but not limited to the following, is considered investigational, experimental, and/or not medically necessary for use in prenatal screening:
  • First-trimester maternal serum anti-Mullerian hormone level
  • First-trimester maternal serum placental growth factor level
  • Maternal plasma microRNA
  • First-trimester maternal plasma levels of follistatin-related gene protein
• Ultrasound evaluation of the right subclavian artery (RSA)
  • Rationale: A 2008 study by Zalel et al. looked at the utility of aberrant subclavian artery with ultrasound as a marker of Down syndrome. They found that 37.5% of fetuses with Down Syndrome had an aberrant right subclavian artery, and 1.4% without Down syndrome. However, they concluded that "Larger prospective studies are needed to examine the significance of ARSA as an isolated finding and the potential of ARSA as a marker in Down syndrome screening."

Prenatal Lead Level Testing

Prenatal lead level testing is considered not medically necessary in women without risk factors for lead exposure.

Rationale: The Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) do not recommend blood lead testing of all pregnant women unless at least one risk factor is present for elevated lead levels.