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National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, the most 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. Non-invasive prenatal screening (NIPS) analyzing cell-free fetal DNA in maternal serum is a potential complement or alternative to conventional serum screening. NIPS using cell-free DNA has also been proposed to screen for microdeletions.
Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. Most fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving 3 copies of one chromosome. The most important risk factor for trisomy syndromes is maternal age. The approximate risk of a trisomy 21 (T21; Down syndrome)--affected birth is 1 in 1100 at age 25 to 29. The risk of a fetus with T21 (at 16 weeks of gestation) is about 1 in 250 at age 35 and 1 in 75 at age 40.
T21 is the most common cause of human birth defects and provides the impetus for current maternal serum screening programs. Other trisomy syndromes include T18 (Edwards syndrome) and T13 (Patau syndrome), which are the next most common forms of fetal aneuploidy, although the percentage of cases surviving to birth is low and survival beyond birth is limited. The prevalence of these other aneuploidies is much lower than the prevalence of T21, and identifying them is not currently the main intent of prenatal screening programs. Also, the clinical implications of identifying T18 and T13 are unclear because survival beyond birth is limited for both conditions.
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. Standard aneuploidy screening involves combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy. 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 could improve outcomes. Confirmation of positive non-invasive screening tests with amniocentesis or CVS is recommended; with more accurate tests, fewer women would receive positive screening results.
Commercial, non-invasive, sequencing-based testing of maternal serum for fetal trisomy syndromes is now available. 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 amplified by polymerase chain reaction; 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 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.
At least some of the commercially available cell-free DNA prenatal tests also test for other abnormalities including sex chromosome abnormalities and selected microdeletions. Sex chromosome aneuploidies (eg, 45,X [Turner syndrome]; 47,XXY, 47,XYY) occur in approximately 1 in 400 live births. These aneuploidies are typically diagnosed postnatally, sometimes not until adulthood, such as during an evaluation of diminished fertility. Alternatively, sex chromosome aneuploidies may be diagnosed incidentally during invasive karyotype testing of pregnant women at high risk for Down syndrome. Potential benefits of early identification (eg, the opportunity for early management of the manifestations of the condition), must be balanced against potential harms that can include stigmatization and distortion of a family’s view of the child.
Microdeletions (also known as submicroscopic deletions) are defined as chromosomal deletions that are too small to be detected by microscopy or conventional cytogenetic methods. They can be as small as 1 and 3 megabases (Mb) long. Microdeletions, along with microduplications, are collectively known as copy number variations (CNVs). CNVs can lead to disease when the change in copy number of a dose-sensitive gene or genes disrupts the ability of the gene/s to function and effects the amount of protein produced. A number of genomic disorders associated with microdeletion have been identified. The disorders have distinctive and, in many cases, serious clinical features, such as cardiac anomalies, immune deficiency, palatal defects, and developmental delay as in DiGeorge syndrome. Some of the syndromes such as DiGeorge have complete penetrance yet marked variability in clinical expressivity. Reasons for the variable clinical expressivity are not entirely clear. A contributing factor is that the breakpoints of the microdeletions may vary, and there may be a correlation between the number of haplo-insufficient genes and phenotypic severity.
A proportion of microdeletions are inherited and some are de novo. Accurate estimates of the prevalence of microdeletion syndromes during pregnancy or at birth are not available. Risk of a fetus with a microdeletion syndrome is independent of maternal age. There is little population-based data and most studies published to date base estimates on phenotypic presentation. The 22q11.2 (DiGeorge) deletion is the most common microdeletion associated with a clinical syndrome. According to the GeneTests database, current estimates of prevalence range from 1 in 4000 to 1 in 6395 live births. Prevalence estimates for other microdeletions are between 1 in 5000 and 1 in 10,000 live births for 1p36 deletion syndrome, between 1 in 10,000 and 1 in 30,000 for Prader-Willi syndrome, and between 1 in 12,000 and 1 in 24,000 for Angelman syndrome. The above figures likely underestimate the prevalence of these microdeletion syndromes in the prenatal population because the population of mutation carriers includes phenotypically normal or very mildly affected individuals.
Routine prenatal screening for microdeletion syndromes is not recommended by national organizations. Current practice is to offer invasive prenatal diagnostic testing in selected cases to women when a prenatal ultrasound indicates anomalies (eg, heart defects, cleft palate) that could be associated with a particular microdeletion syndrome. Samples are analyzed using fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), or karyotyping. In addition, families at risk (eg, those known to have the deletion or with a previous affected child) generally receive genetic counseling and those who conceive naturally may choose prenatal diagnostic testing. Most affected individuals, though, are identified postnatally based on clinical presentation and may be confirmed by genetic testing. Using 22q11.2 deletion syndrome as an example, although clinical characteristics vary, palatal abnormalities (eg, cleft palate) occur in approximately 69% of individuals, congenital heart disease in 74%, and characteristic facial features are present in a majority of individuals of northern European heritage.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (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. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of non-invasive prenatal screening tests using cell-free fetal DNA. Commercially available tests include but are not limited to the following:
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 singleton pregnancies 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].)
Concurrent nucleic acid sequencing–based testing of maternal plasma for trisomy 13 and/or 18 may be considered medically necessary in women who are eligible for and are undergoing nucleic acid sequencing–based testing of maternal plasma for trisomy 21.
Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered investigational in women with twin or multiple pregnancies.
Nucleic acid sequencing–based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above, is considered investigational.
Nucleic acid sequencing–based testing of maternal plasma for fetal sex chromosome aneuploidies is considered investigational.
Nucleic acid sequencing-based testing of maternal plasma for microdeletions is considered investigational.
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 does not apply to pregnancies with a high clinical suspicion of fetal microdeletions for which invasive confirmatory testing is indicated.
In a 2015 committee opinion, the American College of Obstetricians and Gynecologists (ACOG) recommends that all patients receive information on the risks and benefits of various methods of prenatal screening and diagnostic testing for fetal aneuploidies, including the option of no testing.
Studies published to date on non-invasive prenatal screening for fetal aneuploidies 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. False-positive findings have been found to be associated with factors including placental mosaicism, vanishing twins, and maternal malignancies. In its 2015 committee opinion, ACOG recommended diagnostic testing to confirm positive cell-free DNA tests, and that management decisions not be based solely on the results of cell-free DNA testing. ACOG further recommends that patients with indeterminate or uninterpretable (ie, “no call”) cell-free DNA test results be referred for genetic counseling and offered ultrasound evaluation and diagnostic testing because “no call” findings have been associated with an increased risk of aneuploidy.
As noted in the 2015 ACOG committee opinion, cell-free DNA screening does not assess risk of anomalies such as neural tube defects. Patients should continue to be offered ultrasound or maternal serum alpha-fetoprotein screening, regardless of the type of serum screening selected.
In some cases, tissue samples from chorionic villous sampling (CVS) or amniocentesis may be insufficient for karyotyping; confirmation by specific fluorescent in situ hybridization (FISH) assay is acceptable for these samples.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
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.
11/13/2015: Policy title changed from "Sequencing-based Tests to Determine Trisomy 21 from Maternal Plasma DNA" to "Noninvasive Prenatal Screening for Fetal Aneuploidies and Microdeletions Using Cell-Free Fetal DNA." Policy description updated regarding microdeletions and available tests. Medically necessary statement regarding nucleic acid sequencing-based testing updated to change "high-risk singleton pregnancies" to "singleton pregnancies." Removed not medically necessary statement regarding women with average-risk singleton pregnancies. Added the following policy statements: 1) Concurrent nucleic acid sequencing–based testing of maternal plasma for trisomy 13 and/or 18 may be considered medically necessary in women who are eligible for and are undergoing nucleic acid sequencing–based testing of maternal plasma for trisomy 21. 2) Nucleic acid sequencing–based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above, is considered investigational. Added two policy statements to state that nucleic acid sequencing-based testing of maternal plasma for fetal sex chromosome aneuploidies and microdeletion are considered investigational. Policy guidelines updated to remove information regarding high-risk singleton pregnancies; added ACOG recommendations and information regarding genetic counseling. Medically necessary and investigative definitions added.
05/27/2016: Policy number added.
06/22/2016: Code Reference section updated to add the following ICD-10 diagnosis codes as covered: O09.891, O28.5, Z34.01, Z34.81, and Z36.
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.