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National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, the majority of which are aneuploidies (an abnormal number of chromosomes). The trisomy syndromes are aneuploidies involving 3 copies of one chromosome. Trisomies 21, 18, and 13 are the most common forms of fetal aneuploidy that survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Commercial non-invasive, sequencing-based testing of maternal serum for fetal trisomy 21, 18, and 13 has recently become available and has the potential to substantially alter the current approach to screening.
Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. The majority of fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving 3 copies of one chromosome. Trisomy 21 (Down syndrome, T21), trisomy 18 (Edwards syndrome, T18), and trisomy 13 (Patau syndrome, T13) are the most common forms of fetal aneuploidy that survive to birth. The most important risk factor for Down syndrome is maternal age, with an approximate risk of 1/1,500 in young women that increases to nearly 1/10 by age 48.
Current national guidelines recommend that all pregnant women be offered screening for fetal aneuploidy (referring specifically to trisomy 21, 18, and 13) before 20 weeks of gestation, regardless of age. Combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy are used, but there is not a standardized approach. The detection rate for various combinations of non-invasive testing ranges from 60-96% when the false positive rate is set at 5%. When tests indicate a high risk of a trisomy syndrome, direct karyotyping of fetal tissue obtained by amniocentesis or chorionic villous sampling (CVS) is required to confirm that trisomy 21 or another trisomy is present. Both amniocentesis and CVS are invasive procedures and have an associated risk of miscarriage. A new screening strategy that reduces unnecessary amniocentesis and CVS procedures and increases detection of trisomy 21, 18, and 13 has the potential to improve outcomes.
Commercial, non-invasive, sequencing-based testing of maternal serum for fetal trisomy syndromes has recently become available and has the potential to substantially alter the current approach to screening. The test technology involves detection of fetal cell-free DNA fragments present in the plasma of pregnant women. As early as 8 to 10 weeks of gestation, these fetal DNA fragments comprise 6% to 10% or more of the total cell-free DNA in a maternal plasma sample. The tests are unable to provide a result if fetal fraction is too low, that is, below about 4%. Fetal fraction can be affected by maternal and fetal characteristics. For example, fetal fraction was found to be lower at higher maternal weights and higher with increasing fetal crown-rump length.
Sequencing-based tests use 1 of 2 general approaches to analyzing cell-free DNA. The first category of tests uses quantitative or counting methods. The most widely used technique to date uses massively parallel shotgun sequencing (MPS; also known as next generation or “next-gen” sequencing). DNA fragments are first amplified by polymerase chain reaction (PCR); during the sequencing process, the amplified fragments are spatially segregated and sequenced simultaneously in a massively parallel fashion. Sequenced fragments can be mapped to the reference human genome in order to obtain numbers of fragment counts per chromosome. The sequencing-derived percent of fragments from the chromosome of interest reflects the chromosomal representation of the maternal and fetal DNA fragments in the original maternal plasma sample. Another technique is direct DNA analysis, which analyzes specific cell-free DNA fragments across samples and requires approximately a tenth the number of cell-free DNA fragments as MPS. The digital analysis of selected regions (DANSR™) is an assay that uses direct DNA analysis.
The second general approach is single-nucleotide polymorphism (SNP)-based methods. These use targeted amplification and analysis of approximately 20,000 SNPs on selected chromosomes (eg, 21, 18 and 13) in a single reaction. A statistical algorithm is used to determine the number of each type of chromosome.
In order to be clinically useful, the technology must be sensitive enough to detect a slight shift in DNA fragment counts among the small fetal fragment representation of a genome with a trisomic chromosome against a large euploid maternal background. Whether sequencing-based assays require confirmation by invasive procedures and karyotyping depends on assay performance. However, discrepancies between sequencing and invasive test results that may occur for biological reasons could make confirmation by invasive testing necessary at least in some cases, regardless of sequencing test performance characteristics.
None of the commercially available sequencing assays for detection of trisomy 21, 18 and 13 or other chromosomal abnormalities has been submitted to or reviewed by the U.S. Food and Drug Administration (FDA). Clinical laboratories may develop and validate tests in-house (laboratory-developed tests or LDTs; previously called “home-brew”) and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories offering LDTs must be licensed by CLIA for high-complexity testing. Information on commercially available tests is as follows:
A related medical policy is First-Trimester Detection of Down Syndrome Using Fetal Ultrasound Markers Combined with Maternal Serum Assessment.
Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 may be considered medically necessary in women with high-risk singleton pregnancies (see Policy Guidelines) undergoing screening for trisomy 21. (Karyotyping would be necessary to exclude the possibility of a false positive nucleic acid sequencing–based test. Before testing, women should be counseled about the risk of a false positive test. See Policy Guidelines.)
Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered not medically necessary in women with average-risk singleton pregnancies.
Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered investigational in women with twin or multiple pregnancies.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
High-risk singleton pregnancies, as defined by the American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, Number 454, December 2012 include women who meet at least one of the following criteria:
This policy focuses on detection of trisomy 21, as it is the most common cause of human birth defects and provides the impetus for current maternal serum screening programs. Detection of trisomy 21 by DNA-based sequencing methods would likely be representative of the testing technology and interpretation for autosomal trisomy detection such as trisomy 18 and 13 (but not for aneuploidies of sex chromosomes). However, screening for these other trisomy syndromes is not currently the main intent of prenatal screening programs. The prevalence of other trisomy syndromes is much lower than the prevalence of trisomy 21. Also, the clinical implications of identifying trisomy 18 and 13 are unclear, as most fetuses with trisomy 18 and 13 do not survive to term.
Studies published to date report rare but occasional false positives. In these studies, the actual false positive test results were not always borderline; some were clearly above the assay cutoff value, and no processing or biological explanations for the false positive results were reported. In the decision model conducted for the 2012 TEC Assessment, using an overall estimate for predictive value calculations, even in a high risk population, the predictive value of a positive result was only 83%. Thus, in the absence of substantial data to confidently characterize the false positive rate, a karyotyping test would be necessary to confirm a positive result.
In some cases, tissue samples from CVS or amniocentesis may be insufficient for karyotyping; confirmation by specific fluorescent in situ hybridization (FISH) assay is acceptable for these samples.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY03/21/2013: Approved by Medical Policy Advisory Committee.
08/01/2013: Added CPT code 81479 to the Code Reference section. Added the following ICD-9 codes to the Code Reference section: 655.10, 655.11, 655.13, 659.50, 659.53, 659.60, 659.63, 758.5, V23.81, and V23.82.
02/18/2014: Added the following new 2014 CPT code(s) to the Code Reference section: 81507.
03/11/2014: Policy reviewed; description updated. Policy statement unchanged.
06/19/2014: Policy reviewed; description updated regarding fetal fraction and general approaches to analyzing cell-free DNA using sequencing-based tests. Policy statement unchanged.
12/31/2014: Added the following new 2015 CPT code to the Code Reference section: 81420.
08/26/2015: Medical policy revised to add ICD-10 codes.
SOURCE(S)Blue Cross Blue Shield Association policy # 4.01.21
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.