Invasive Prenatal Diagnosis of Genetic Diseases - Medical Clinical Policy Bulletins (2024)

Number:0358

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses invasive prenatal diagnosis of genetic diseases.

1. Medical Necessity

   1. Aetna considers the following medically necessary:

      1. Invasive prenatal diagnosis by chorionic villus sampling (CVS), genetic amniocentesis, and percutaneous umbilical blood sampling (PUBS) (cordocentesis) for diagnosis of fetal chromosomal abnormalities.
      2. Preimplantation genetic testing for monogenic disorders (PGT-M) (formerly called preimplantation genetic diagnosis [PGD]) which detects specific genetic diseases (usually autosomal recessive conditions) by using molecular analysis techniques on single cells removed from the embryo. PGT-M / PGDon single cells is considered medically necessary when all of the following criteria are met:
         1. Technical and clinical performance of the genetic test is supported by published peer-reviewed medical literature; and
         2. PGT-M /PGD is performed for any of the followingindications:
            1. To diagnose an autosomal dominant condition when at least one parent is a known carrier; or
            2. To diagnose an autosomal recessive condition when both parents are known carriers (e.g., cystic fibrosis when parents are known mutation carriers); or
            3. To diagnose an X-linked condition when at least one parent is a known carrier (e.g., hemophilia) (Note: If PGT-M /PGD is requested for evaluation of Fragile X syndrome, medical necessity criteria are met if one parent is a known carrier of more than 55 triplet repeats of the Fragile X gene, which is associated with risk for disease in the offspring); or
            4. To diagnose an embryo at risk for a disease-causing chromosome rearrangementwhen one parent is a known carrier of a balanced (e.g. Robertsonian translocation, inversion) or unbalanced chromosomal rearrangement (e.g. insertion, deletion) translocation; and
               
         3. Results of genetic testing will directly impact and change management of the individual being tested who is a covered member; and
         4. The PGT-M /PGD procedure will eliminate the need for subsequent invasive prenatal diagnosis by genetic amniocentesis or CVS; and
         5. A specific mutation, or set of mutations, has been identified, that specifically identifies the genetic disease with a high degree of reliability; and
         6. The genetic disease is associated with clinically significant morbidity or disability.

      Aetna considers PGT-M /PGD not medically necessary for sex selection for non-medical purposes.

      Note:PGT-M (formerly called PGD) and Preimplantation genetic testing for aneuploidy (PGT-A) (formerly called preimplantation genetic screening [PGS])are performed on embryos produced after IVF cycles. The methods used to retrieve PGT-M (PGD) material from embryos are the same, irrespective of the type of genetic analysis required. The biopsy procedure entails micro-manipulation and special techniques are used to avoid contamination from exogenous DNA (e.g., cellular DNA from non-fertilizing sperm) in the IVF laboratory. However, for carriers of single gene disorders (e.g., cystic fibrosis, spinal muscular atrophy) where polymerase chain reaction [PCR] will be applied, ICSI is considered medically necessary to avoid contamination from non-fertilizing sperm for members with the ART benefit. The procedure to obtain the cell sample for PGT-M / PGD (i.e., the embryo biopsy) is considered medically necessary when criteria for PGT-M / PGD are met. However, the IVF procedure (i.e., the procedures and services required to create the embryos to be tested and the transfer of the appropriate embryos back to the uterus after testing) is covered only for persons with ART benefits who meet medical necessity criteria for IVF outlined in CPB 0327 - Infertility. Please check benefit plan descriptions.

   2. Aetna considers conventional cytogenetic analysis and quantitative fluorescent polymerase chain reaction (QF-PCR) a medically necessary method to detect trisomies whenever prenatal testing is performed solely because of an increased risk of aneuploidy in chromosomes 13, 18, 21, X or Y.

      See Also

      Billing and Coding: Cardiology Non-emergent Outpatient Stress Testing (A56423)
      1. Both conventional cytogenetics and QF-PCR are considered medically necessary in all cases of prenatal diagnosis referred for a fetal ultrasound abnormality (including an increased nuchal translucency measurement greater than 3.5 mm) or a familial chromosomal rearrangement.
      2. Cytogenetic follow-up of QF-PCR findings of trisomy 13 and 21 is considered medically necessary to rule out inherited Robertsonian translocations.

      Note: Established nongenetic indications for amniocentesis include assessment of fetal lung maturity, and evaluation of the fetus for infection, degree of hemolytic anemia, blood or platelet type, hemoglobinopathy, and neural tube defects.Amniocentesis is also performed as a therapeutic procedure to remove excess amniotic fluid. See CPB 0449 - Fetal Surgery in Utero.

2. Experimental, Investigational, or Unproven

   Aetna considers the following experimental, investigational, or unproven:

   1. Preimplantation genetic testing for aneuploidy (PGT-A) (formerly called preimplantation genetic screening [PGS])(either too many or too few chromosomes in an embryo), including but not limited to optimization of IVF outcomes, history of failed IVF cycles, or recurrent miscarriages;

      Note: There are multiple ways to perform PGT-A / PGS. Two modalities commonly used are microarray analysis, with single nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) analysis.Another way isthe Igenomix SMART PGT-A (Preimplantation Genetic Testing - Aneuploidy) Test, which entails the analysis of 24 chromosomes using embryonic DNA genomic sequence analysis for aneuploidy, and a mitochondrial DNA score in euploid embryos.

   2. Invasive prenatal screening and preimplantation genetictesting for aVUS (also known as unclassified variant or variant of uncertain significance);
   3. IriSight Prenatal Analysis;
   4. Multigene panels at time ofPGT-M / PGD testing;
   5. PGT-M/ PGD for fetal chromosomal abnormalities because the procedure is not as accurate as cytogenetic analysis performed on prenatal diagnosis specimens obtained by CVS or amniocentesis;
   6. PGT-M / PGD to determine the human leukocyte antigen (HLA) or other marker status of an embryo as a potential donor for future stem cell transplant because PGT-M / PGD has not been established as the standard of care for assessing the suitability of embryos for stem cell transplantation;
   7. Natera Spectrum PGT-M (preimplantation genetic testing for monogenic disorders) due to insufficient evidence of technical and clinical performance in published peer-reviewed medical literature.

3. Related Policies

   • CPB 0282 - Noninvasive Down Syndrome Screening
   • CPB 0327 - Infertility
   • CPB 0449 - Fetal Surgery in Utero.
   • CPB 0464 - Serum and Urine Marker Screening for Fetal Aneuploidy

Background

Preimplantation genetic testing (PGT) includes two categories: preimplantation genetic testing for monogenic/single gene disorders (formerly known as preimplantation genetic diagnosis) and preimplantation genetic testing for aneuploidies (formerly known as preimplantation genetic screening). According to the American Society for Reproductive Medicine, the term 'preimplantation genetic diagnosis' (PGD) applies when one or more genetic parents carry a gene mutation or a balanced chromosomal rearrangement and testing is performed to determine whether that specific mutation or an unbalanced chromosomal complement has been transmitted to the oocyte or embryo. PGD, which is now referred to as 'preimplantation genetic testing for monogenic disorders' (PGT-M),is performed on embryos following in vitro fertilization (IVF) to detect genetic disorders prior to implantation into the uterus. With PGT-M, cell(s) are removed from embryos under microscopic guidance, analyzed for the presence of genetic disorders and only the unaffected embryos are implanted into the uterus. PGT-M is used when one or both parents carry a gene mutation and are at high risk of conceiving a child with a particular genetic disease.

The term 'preimplantation genetic screening' (PGS)is now referred to as 'preimplantation genetic testing for aneuploidy'(PGT-A). PGT-Aapplies when the genetic parents are known or presumed to be chromosomally normal and their embryos are screened for aneuploidy. PGT-Aisperformed on embryos following IVF to screen for aneuploidy in parents who have no known chromosomal anomaly, mutation or other geneticabnormality. PGT-Ahas been proposed for individuals at risk for having an increased occurrence of aneuploid embryos, such as women of advanced maternal age and those with a history of recurrent early pregnancy loss or repeated IVF failure.

PGT-M can detect specific genetic diseases (usually autosomal recessive conditions) by using molecular analysis techniques on single cells removed from the embryo. For many conditions, the usual type ofprenatal diagnosis(i.e., chromosomal analysis/karyotyping) is accomplished on multiple cells obtained by chorionic villus sampling (CVS) or genetic amniocentesis. PGT-M on single cells is considered medically necessary only when there is a need to diagnose specific, detectable single gene mutations (e.g., molecular diagnosis of hereditary disease such as cystic fibrosis when parents are known mutation carriers or fragile X syndrome when the mother is a known carrier) in persons with genetic disorders for whom the PGT-M (PGD) procedure will eliminate the need for subsequent invasive prenatal diagnosis by genetic amniocentesis or CVS. PGT-M for fetal chromosomal abnormalities is currently not as accurate as cytogenetic analysis performed on prenatal diagnosis specimens obtained by CVS or amniocentesis; therefore PGT-M is considered experimental and investigational for that indication.

The diagnosis of fragile X syndrome and other FMR1 disorders is established through the use of specialized molecular genetic testing to detect CGG trinucleotide repeat expansion in the 5' UTR of FMR1 with abnormal gene methylation for most alleles with >200 repeats. Typically, a definite diagnosis of FXS requires the presence of a full-mutation repeat size (>200 CGG repeats) while the diagnosis of FXTAS or FXPOI is associated with a premutation-sized repeat (55-200 CGG repeats).

According to the literature, the accuracy of single gene testing conducted on single cells is thought to be as accurate using PGT-Aprocedures as it would be on cell samples obtained by conventional CVS or amniocentesis. However,PGT-Aprocedures have not been shown to be as accurate as conventional techniques for diagnosing chromosomal errors. Because preimplantation genetic diagnostic procedures are less accurate in detecting chromosomal abnormalities (detecting up to 95% of chromosomal errors using fluorescent in-situ hybridization (FISH) techniques, versus 100% detection with analysis of full karyotype),CVS or amniocentesis is usually necessary to confirm the results of FISH-based PGT-Mcytogenetic procedures.

PGT-A, formerly known as'preimplantation genetic diagnosis-aneuploidy screening' (PGD-AS) and PGS for fetal aneuploidy, involves in-vitro genetic testing of embryos to detect numerical chromosomal abnormalities (aneuploidies). PGD-AS has been investigated as a method of increasing the effectiveness of in-vitro fertilization (IVF) by increasing the live birth rate and reducing the risk of complications from IVF. Miscarried fetuses are often found to have an aneuploidy, as most aneuploides are not compatible with life. Aneuploides have also be found in aborted embryos created by means of IVF. Clinical research is currently being conducted to find out whether PGD-AS can increase the likelihood of live birth from each implanted embryo in IVF. By increasing the likelihood of a live birth from each implanted embryo, PGD-AS has the potential to decrease the need to implant2 embryos instead of 1, thus reducing the risk of multiple pregnancy from IVF and its attendant complications. PGD-AS is also being investigated for use in women undergoing IVF as an alternative to standard methods of prenatal diagnosis of Down syndrome and other aneuploides.

A systematic evidence review of PGD-AS by the Health Council of the Netherlands (GR, 2007) found "little useful research data" on the effect, reliability and safety of PGD-AS. The assessment reported that small-scale studies of PGD-AS have been conducted in women with repeated implantation failure, with recurrent miscarriage, and in women of advanced maternal age; the assessment found that these studies "do not point to any marked improvement in the likelihood of pregnancy." The assessment also found that it "remains unclear" whether PGD-AS is an effective alternative to prenatal diagnosis. The assessment concluded that "[m]ore data is needed before [PGD-AS] can be carried out or offered as a matter of routine." The assessment noted that, if further research established that PGD-AS increases the success rate of IVF, it will be important to clearly establish the indications for PGD-AS and to assure its quality and safety.

In a literature review, Shulman (2003) stated that fetal cells in maternal blood represent the future of prenatal screening and diagnosis. The possibility of analyzing fetal cells recovered from maternal blood could provide screening and diagnostic protocols characterized by high sensitivity and specificity with no direct risk to the developing fetus. However, years of research have thus far not led to the development of reliable and consistent protocols.

In a review, Sierra and Stephenson (2006) stated that research has generated interest in genetic markers for recurrent pregnancy loss such as skewed X-chromosome inactivation and human leukocyte antigen-G polymorphisms. Assisted reproductive technologies, in particular, PGD have been offered to couples with recurrent pregnancy loss; however, more research is need before their routine use can be advocated. This is in agreement with the observation of Shahine and Cedars (2006) who noted that although analysis with PGD confirms a high rate of aneuploidy in patients with advanced maternal age, recurrent pregnancy loss, and recurrent IVF failure, its use in these patient populat