Medical Policy: 02.04.38 

Original Effective Date: February 2016 

Reviewed: February 2017 

Revised: February 2017 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. Most fetal abnormalities are aneuploidies, defined as an abnormal number of chromosomes, which are the structures that contain genetic information. The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome, trisomies 21 (Down syndrome), 18 (Edwards syndrome), and 13 (Patau syndrome) are the most common aneuploidies. Trisomy 21 is the most frequent occurring, followed by trisomy 18 then trisomy 13. A risk of having a baby with Down syndrome increases with maternal age, significantly after age 35. However, age cannot serve as the sole screening factor as a high percentage of Down syndrome babies are born to women under the age of 35. 

 

Current national guidelines recommend that all pregnant women be offered screening for fetal aneuploidy (referring specifically to T21, T18 and T13) 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 noninvasive testing ranges from 60% to 96% when the false-positive rate is set at 5%. When tests indicate a high risk of trisomy syndrome, direct karyotyping of fetal tissue obtained by amniocentesis or chronic villous sampling (CVS) is required to confirm that T21 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 T21, T18 and T13 could improve outcomes. Confirmation of positive noninvasive screening tests with amniocentesis or CVS is recommended; with more accurate tests, fewer geno typical women could receive positive screening results.

 

Commercial, noninvasive, 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 test 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, also referred to as noninvasive prenatal testing (NIPT) has been investigated as a method of detecting common fetal aneuploidy including trisomies 21, 18 and 13 in high risk pregnancies (e.g. advanced maternal age, abnormal fetal ultrasound). This testing method relies on the presence of circulating fetal or cell-free DNA in the maternal plasma during pregnancy.

 

Sequencing-based tests use 1 to 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 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 (e.g., 21, 18, 13) in a single reaction. A statistical algorithm is used to determine the number of each type of chromosome.

 

Analytic Validity of Available Maternal Plasma DNA Sequencing-Based Tests

No studies were identified that provided direct evidence on analytic validity. Each of the commercially available tests use massively parallel sequencing (MPS; also called next-generation sequencing [NGS]), a relatively new technology but not an entirely new concept for the clinical laboratory. Currently, there are no recognized standards for conducting clinical sequencing by MPS. On June 23, 2011, the U.S. Food and Drug Administration (FDA) held an exploratory, public meeting on MPS, in preparation for an eventual goal of developing “a transparent evidence-based regulatory pathway for evaluating medical devices/products based on next generation sequencing, NGS, that would assure safety and effectiveness of devices marketed for clinical diagnostics.” The discussion pointed out the difference among manufacturers’ sequencing platforms and the diversity of applications, making it difficult to generate specific regulatory phases and metric. It was suggested that “the process may need to be judged by the accuracy and fidelity of the final result.” A consistent discussion trend was that validation be application specific. Thus, technical performance may need to be more closed linked to intended use and population and may not be generalizable across all sequencing applications. Each of the companies currently offering a maternal plasma DNA sequencing test has developed a specific procedure for its private, Clinical Laboratory Improvement Act-licensed laboratory where all testing takes place.

 

Although all currently available commercial tests use MPS, actual performance and interpretive procedures vary considerably. Clinical sequencing in general is not standardized or regulated by Food and Drug Administration or other regulatory agencies, and neither the routine quality control procedures used for each of these tests, nor the analytic performance metrics have been published.

 

Clinical Utility of Available Maternal Plasma DNA Sequencing-Based Tests for Aneuploidy

The 2013 and 2014 BlueCross BlueShield Association TEC Assessments each constructed decision models to predict health outcomes of sequencing-based testing compared with standard testing. The model in the 2013 TEC assessment focused on T21. In this model, the primary health outcomes of interest included the number of cases of aneuploidy correctly identified, number of cases missed, number of invasive procedures potentially avoided (ie, with a more sensitive test), and the number of miscarriages potentially avoided as a result of fewer invasive procedures. The results were calculated for a high-risk population of women age 35 years or older (estimated antenatal prevalence of T21, 0.95%), and an average-risk population including women of all ages electing an initial screen (estimated antenatal prevalence of T21, 0.25%). For women testing positive on initial screen and offered an invasive, confirmatory procedure, it was assumed that 60% would accept amniocentesis or CVS. Sensitivities and specificities for both standard and sequencing-based screening tests were varied to represent the range of possible values; estimates were taken from published studies whenever possible.

 

According to the model results, sequencing-based testing improved outcomes for both high-risk and average-risk women. As an example, assuming there are 4.25 million births in the United States per year and two-thirds of the population of average-risk pregnant women (2.8 million) accepted screening, the following outcomes would occur for the 3 screening strategies under consideration:

  • Standard screening. Of the 2.8 million screened with the stepwise sequential screen, 87,780 would have an invasive procedure (assuming 60% uptake after a positive screening test and a recommendation for confirmation), 448 would have a miscarriage, and 3976 of 4200 (94.7%) T21 (Down syndrome) cases would be detected.
  • Sequencing as an alternative to standard screening. If sequencing-based testing were used instead of standard screening, the number of invasive procedures would be reduced to 7504 and the number of miscarriages reduced to 28, while the cases of Down syndrome detected would increase to 4144 of 4200 (97.6% of total), using conservative estimates.
  • Sequencing following standard screening. Another testing strategy would be to add sequencing-based testing only after a positive standard screen. In this scenario, invasive procedures would be further decreased to 4116, miscarriages would remain at 28, but fewer Down syndrome cases would be detected (3948/4200 [94.0% of total]). Thus, while this strategy has the lowest rate of miscarriages and invasive procedures, it detects fewer cases than sequencing-based testing alone. 

The model in the 2014 TEC Assessment included T13 and T18 (but not sex chromosome aneuploidies, due to the difficulty of defining relevant health outcomes). The model was similar but not identical to that previously used to evaluate T21. As in earlier model, outcomes of interest included the number of cases of aneuploidy correctly detected and the number of cases missed, and findings were calculated separately for a high-risk population of women aged 35 or older and a low-risk population. The model assumed that 75% of high-risk and 50% of low-risk women who tested positive on the initial screen would proceed to an invasive test. (The T21 model assumed a 60% uptake rate of invasive confirmatory testing.) A distinctive feature of the 2014 modelling study was that it assumed screening for T21 was done concurrently to screening for T13 and T18 and that women who choose invasive testing do so because of a desire to detect T21. Consequently, miscarriages associated with invasive testing were not considered an adverse effect of T13 or T18 screening.

 

The model compared 2 approaches to screening: (1) a positive sequencing-based screen followed by diagnostic invasive testing; and (2) a positive standard noninvasive screen followed by diagnostic invasive testing. As in the T21 modelling study, sensitivities and specificities for both standard and sequencing-based screening tests were varied to represent the range of possible values; estimates were taken from published studies whenever possible. Assuming that a hypothetical population of 100,000 pregnant women was screened, the model had the following findings:

  • High-risk women: Assuming 75% uptake after a positive screen, the maximum cases detectable in the hypothetical population of 100,000 pregnancies is 127 trisomy 18 cases and 45 trisomy 13 cases. Standard noninvasive screening would identify 123 of the 127 trisomy 18 cases and sequencing-based screening would identify 121 of 127 cases. In addition, standard noninvasive screening would identify 37 of 45 trisomy 13 cases and sequencing-based screening would identify 39 of 45 trisomy 13 cases.
  • Low-risk women: Assuming 50% uptake after a positive screen, the maximum cases detectable in the hypothetical population of 100,000 pregnancies is 20 trisomy 18 cases and 6 trisomy 13 cases. Each initial screening test would identify 19 of the 20 trisomy 18 cases and 5 of the 6 trisomy 13 cases.

Results of the modeling suggest that sequencing-based tests detect a similar number of T13 and T18 cases and miss fewer cases than standard noninvasive screening. Even in a hypothetical population of 100,000 women, however, the potential number of detectable cases is low, especially for T13 and for low-risk women.

 

Modeling studies using published estimates of diagnostic accuracy and other parameters predict that sequencing-based testing as an alternative to standard screening will lead to an increase in the number of Down syndrome cases detected and, when included in the model, a large decrease in the number of invasive tests and associated miscarriages. The number of T18 and T13 cases detected is similar or higher with sequencing-based testing, although this is more difficult to estimate because of the lower prevalence of these aneuploidies, especially with T13. The impact of screening for sex chromosome aneuploidies has not been modeled in published studies.

 

High Risk and Average Risk Pregnancies

The available evidence in the published peer reviewed medical literature evaluating the accuracy of clinical utility of sequencing circulating cell-free DNA testing for chromosomal abnormalities consists of validation and cohort studies. These studies have primarily included pregnant women at increased risk for fetal aneuploidy. Fewer studies have been published on maternal plasma DNA sequencing-based tests for detection of T21 in average risk women. The studies conducted in average risk women identified a small number of trisomies and did not confirm negative or positive findings in all cases. Therefore, the evidence of accuracy of sequencing based testing is less definitive for women with average risk pregnancies as it is for women with high risk pregnancies.   

Multiple Gestations

Regardless of the method, the accuracy of screening for aneuploidy is limited in multiple gestations. With any method based on maternal blood (serum analytes of DNA), only a single composite result for the entire gestation is provided, with no ability to distinguish a differential risk between fetuses. The data regarding the performance of cell-free DNA screening in twin gestations are limited. Although preliminary findings suggest that this screening is accurate, larger prospective studies and published data are needed before this method can be recommended for multiple gestations. Cell-free DNA is not recommended for geno typical women with multiple gestations. There are no available data on higher-order multiples.  

 

Summary

High Risk and Average/Low Risk Singleton Pregnancies

There is sufficient evidence in the published, peer reviewed medical literature demonstrating the accuracy and clinical utility of cell-free fetal DNA or sequencing based trisomy testing for maternal blood for the detection of chromosomal abnormalities in a subset of women with a pregnancy at high risk for aneuploidy. Although studies have not addressed improved health outcomes associated with this testing, results obtained from cell-free fetal DNA testing can be used to guide decisions regarding the necessity of invasive testing. With consistently high (i.e. 99% - 100%) sensitivity, specificity, and negative predictive values, no further test is indicated for negative test result. A positive test result does require confirmatory follow-up with amniocentesis or chronic villus sampling. Cell-free fetal DNA testing for aneuploidy has been proven to be accurate and resproducible in the population of women with pregnancies at high risk for aneuploidy. However further well-designed clinical trials are needed to further define the role of this testing in routine pregnancy management as compared to the current standard evaluation of serum biomarkers with or without ultrasonic measurement of nuchal translucency, followed by invasive testing as indicated. Currently the quality and quantity of evidence does not support the use of cell-free fetal DNA testing for pregnancies at average risk for aneuploidy or multiple gestations. Therefore the use of cell-free fetal DNA testing for high risk singleton pregnancies would be considered medically necessary and the use of cell free fetal DNA testing for all other indications to include average risk singleton pregnancies would be considered investigational.             

 

The findings of a decision analysis study included in the 2014 BlueCross BlueShield Association TEC assessment suggest similar rates of T13 and T18 detection to standard noninvasive screening; the analysis assumed that T13 and T18 screening would be done in conjunction with the T21 screening. Due to low survival rate, the clinical benefit of identifying trisomy 18 and 13 are unclear. Therefore, NIPT using cell-free DNA for T18 and T13 are considered medically necessary in women who are eligible for and are undergoing testing of maternal plasma for T21 and investigational otherwise.

 

Twin and Multiple Gestation Pregnancies

The data regarding the performance of NPIT using cell-free DNA screening in twin gestations are limited. Although preliminary findings suggest that this screening is accurate, larger prospective studies and published data are needed before this method can be recommended for multiple gestations. Cell-free DNA is not recommended for women with multiple gestations and there is no available data on higher-order multiples.  
Therefore, the evidence is insufficient to determine the effects of this technology on net health outcomes and is considered investigational.

Testing for Other Genetic Conditions with Cell-Free DNA

Some of the commercially available cell-free DNA prenatal tests also test for other abnormalities including sex chromosome abnormalities and selected microdeletions.

 

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 microdeletions 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.  Examples of microdeletion syndromes include: DiGeorge syndrome or velocardiofacial syndrome (most common), Prader-Willi syndrome, Angelman syndrome, Neurofibromatosis type I, Neurofibromatosis type II, Williams syndrome, Miller-Dieker syndrome, Smith-Magenis syndrome, Rubinstein-Taybi syndrome and Wolf-Hirschhorn syndrome.  

 

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 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.

 

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 with prenatal ultrasound indicates anomalies (e.g. 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, those known to have the deletion or with a previous affected child generally receive genetic counseling. Most affected individuals are identified postnatally based on clinical presentation and may be confirmed with genetic testing.           

 

Microdeletion testing is currently offered commercially by 2 companies. Several studies on clinical validity of microdeletion testing have been published, based on large numbers of samples submitted to the testing companies. These studies have limitations (e.g. substantial missing data on confirmatory testing, lack of complete data on false negatives). Many of the cases of microdeletion syndromes are currently initially detected via characteristic anomalies seen on prenatal ultrasound. 

 

The clinical utility of testing for any particular microdeletion or any panel of microdeletions is uncertain. There is no direct data on whether sequencing-based testing for microdeletions improve outcomes compared with standard care. The incidence of microdeletions in otherwise normal pregnancies is extremely low, lower than the threshold level of testing established for carrier testing (generally 1%). Further, the incidence of clinical disease is likely lower than the incidence of microdeletion mutations because not all individuals with a microdeletion will have clinical symptoms. Thus, the yield of testing is very low, requiring testing of many patients to identify a small number of cases.

 

There is a potential that prenatal identification of individuals with microdeletion syndromes could improve health outcomes due to the ability to allow for informed reproductive decision making, and/or to initiate earlier treatment; however data demonstrating improvement are unavailable. Given the variability of expressivity of microdeletion syndromes and the lack of experience with routine genetic screening for microdeletions, clinical decision making based on genetic test results is not well defined. It is not clear what follow-up testing or treatments might be indicated for screen-detected individuals. Routine prenatal screening may identify a small percentage of fetuses with microdeletion mutations earlier in pregnancy than would otherwise have occurred (eg, by ultrasound evaluation and diagnostic testing). At the same time, routine prenatal screening for microdeletions would also result in false-positive tests and a larger number of invasive confirmatory tests. The large number of confirmatory tests could lead to a net harm as a result of pregnancy loss.

 

The clinical utility of NIPS for microdeletions remains unclear and has not been evaluated in published studies. The incidence of microdeletions syndromes is low, and not all individuals with microdeletion have clinical symptoms. Clinical follow-up of screen detected microdeletions is unclear and screening has potential associated harms (e.g. pregnancy loss associated with confirmatory tests for positive screens). Given the gaps in the evidence, conclusions cannot be drawn about the impact of this testing on net health outcomes.  


Sex chromosome aneuploidies belong to a group of genetic conditions that are caused or affected by the loss or damage of sex chromosomes (genosomes). This may refer to: 47, XXX; 48, XXXX; 49 XXXXY syndrome; 49, XXXXX; Klinefelter’s syndrome, XXY; Turner syndrome, X; XXX gonadal dysgenesis; XX male syndrome; XXYY syndrome; XYY syndrome. 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 (e.g. 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.   

 

The evidence for NIPS using cell free DNA to detect sex chromosome aneuploidies in individuals pregnant with singletons includes several diagnostic studies. There is less published evidence on the diagnostic performance of sequencing-based tests for detecting fetal sex chromosome anomalies, and most of the available studies were conducted in high-risk pregnancies. Meta-analyses of available data suggests high sensitivities and specificities, but the small number of cases, especially for T13, makes definitive conclusions difficult. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

Genetic Counseling 

Counseling regarding the limitations of cell-free DNA should include a discussion about how the screening methods provide information regarding only trisomies 13, 18, and 21. If a sex chromosome analysis has been requested or is part of the standard panel, then this information should be conveyed as well.

 

Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chronic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Not only can there be false-positive test results, but a positive cell-free DNA test result for aneuploidy does not determine if the trisomy is due to a translocation, which affects the risk of recurrence. If a fetal structural anomaly is identified on ultrasound examination, diagnostic testing should be offered rather than cell-free DNA screening.

 

The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Given the potential for inaccurate results and to understand the type of trisomy for recurrence-risk counseling, a diagnostic test should be recommended for a patient who has a positive cell-free DNA test result. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. False-positive results do occur and diagnostic testing with amniocentesis or chronic villus sampling (CVS) should be recommended before any pregnancy termination decision. Causes of false-positive test results have been reported, which include but are not limited to placental mosaicism, vanishing twins, and maternal malignancies.

 

Before offering cell-free DNA screening, counseling is recommended. The family history should be reviewed to determine if the patient should be offered other forms of screening or prenatal diagnosis for a particular disorder. In order to ensure accuracy and testing of the appropriate patient population, a baseline ultrasound examination also should be considered to confirm viability, the number of fetuses, and gestational dating, if not performed previously. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. A negative test result still carries a residual risk of one of the common trisomies and does not ensure that the fetus does not have another chromosome abnormality or genetic diagnosis. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. Parallel or simultaneous testing with multiple screening methodologies for aneuploidy is not cost effective and should not be performed. However, use of cell-free DNA screening as a follow-up test for patients with positive traditional screening test is reasonable for patients who want to avoid a diagnostic test.

 

Regulatory Status

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 that offer 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 noninvasive prenatal screening tests using cell-free fetal DNA. Commercially available tests include but are not limited to the following:

  • Sequenom MaterniT21™ PLUS test: Tests for trisomy 21, 18, and 13 and fetal sex aneuploidies. Their enhanced sequencing series includes testing for trisomies 16 and 22 and 7 microdeletions: 22q deletion syndrome (DiGeorge syndrome), 5p (cri du chat syndrome), 15q (Prader-Willi and Angelman syndromes), 1p36 deletion syndrome, 4p (Wolf-Hirschhorn syndrome), 8q (Langer-Giedion syndrome), and 11q (Jacobsen syndrome). The test uses massive parallel sequencing (MPS) and reports results as positive or negative. The enhanced sequencing series is offered on an opt-out basis.
  • Ariosa Diagnostics Harmony™ test: (Ariosa was acquired by Roche in January 2015). Tests for trisomies 21, 18, and 13. Uses directed DNA analysis, results reported as risk score.
  • Natera Panorama™ prenatal test: Tests for detecting trisomy 21, 18, and 13, as well as select sex chromosome abnormalities. Uses single-nucleotide polymorphisms technology; results reported as risk score. An extended panel tests for 5 microdeletions: 22q deletion syndrome (DiGeorge syndrome), 5p (cri du chat syndrome), 15q11-13 (Prader-Willi and Angelman syndromes), and 1p36 deletion syndrome. Screening for 22q11.2 will be included in the panel unless the opt-out option is selected; screening for the remaining 4 microdeletions is offered on an opt-in basis.
  • Illumina (formerly Verinata Health, which it acquired) Verifi® prenatal test: Tests for trisomy 21, 18, and 13. The test uses MPS and calculates a normalized chromosomal value [NPS]; reports results as 1 of 3 categories: No Aneuploidy Detected, Aneuploidy Detected, or Aneuploidy Suspected.
  • Integrated Genetics (LabCorp Specialty Testing Group) InformaSeqSM prenatal test: Tests for detecting trisomy 21, 18, and 13, with optional additional testing for select sex chromosome abnormalities. Uses Illumina platform and reports results in similar manner.
  • Quest Diagnostics QNatal™ Advanced: Tests for trisomies 21, 18, and 13.

 

Practice Guidelines and Position Statements

 

The American College of Obstetrician and Gynecologists (ACOG)

In 2012, The American College of Obstetricians and Gynecologists issued a committee opinion, number 545 for noninvasive prenatal testing for fetal aneuploidy that included the following indications for considering the use of cell-free fetal DNA:

  • Maternal age 35 years or older at the time of delivery; OR
  • Fetal ultrasonographic findings indicating an increased risk of aneuploidy; OR
  • History of a prior pregnancy with a trisomy; OR
  • Positive test result for aneuploidy including first trimester, sequential, or integrated screen, or a quadruple screen; OR
  • Either parent has been identified as having a balanced Robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21

Conclusions

  • Patients at increased risk of aneuploidy can be offered testing with cell free fetal DNA. This technology can be expected to identify approximately 98% of cases of Down syndrome with a false-positve rate of less then 0.5%.
  • Cell free fetal DNA testing should not be part of routine prenatal laboratory assessment, but should be an informed patient choice after pretest counseling.
  • Cell free fetal DNA testing should not be offered to low risk women or women with multiple gestations because it has not been sufficiently evaluated in these groups.
  • Pretest counseling should include a review that although the cell free fetal DNA test is not a diagnostic test, it has high sensitivity and specificity. The test will only screen for the common trisomies and, at the present time, gives no other genetic information about the pregnancy.
  • A family history should be obtained before the use of this test to determine if the patient should be offered other forms of screening or prenatal diagnosis for familial genetic disease.
  • If a fetal structural anomaly is identified on ultrasound examination, invasive prenatal diagnosis should be offered.
  • A negative cell free fetal DNA test result does not ensure an unaffected pregnancy.
  • A patient with a positive test result should be referred for genetic counseling and offered invasive prenatal diagnosis for confirmation of test results.
  • Cell free fetal DNA does not replace the accuracy and diagnostic precision of prenatal diagnosis with CVS or amniocentesis, which remains an option for women. 

 

American College of Obstetricians and Gynecologists (ACOG) and Society of Maternal Fetal Medicine

September 2015, ACOG and the Society of Maternal Fetal Medicine related an updated committee opinion (number 640) on cell-free DNA screening for fetal aneuploidy (this document replaces committee opinion number 545). The list of recommendations in the 2015 committee opinion includes the following: 

  • A discussion of the risks, benefits, and alternatives of various methods of prenatal screening and diagnostic testing, including the option of no testing, should occur with all patients.
  • Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population.
  • Although any patient may choose cell-free DNA analysis as a screening strategy for common aneuploidies regardless of her risk status, the patient choosing this testing should understand the limitations and benefits of this screening paradigm in the context of alternative screening and diagnostic options.
  • The cell-free DNA test will screen for only the common trisomies and, if requested, sex chromosome composition.
  • Given the potential for inaccurate results and to understand the type of trisomy for recurrence-risk counseling, a diagnostic test should be recommended for a patient who has a positive cell-free DNA test result.
  • Parallel or simultaneous testing with multiple screening methodologies for aneuploidy is not cost-effective and should not be performed.
  • Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone.
  • Women whose results are not reported, indeterminate, or uninterpretable (a "no call" test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy.
  • Routine cell-free DNA screening for microdeletion syndromes should not be performed.
  • Cell-free DNA screening is not recommended for women with multiple gestations.
  • If a fetal structural anomaly is identified on ultrasound examination, diagnostic testing should be offered rather than cell-free DNA screening.
  • Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy.
  • Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects; patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment.
  • Patients may decline all screening or diagnostic testing for aneuploidy.

 

European Society of Human Genetics and American Society of Human Genetics

In 2015, the public and professional policy committee of the European Society of Human Genetics and the social issues committee of the American Society of Human Genetics issued a joint statement on NIPS (also called noninvasive prenatal testing [NIPT]).  Relevant recommendations are as follows:

  • “NIPT offers improved accuracy when testing for common autosomal aneuploidies compared with existing tests such as cTFS (combined first-trimester screening). However, a positive NIPT result should not be regarded as a final diagnosis: false positives occur for a variety of reasons (including that the DNA sequenced is both maternal and fetal in origin, and that the fetal fraction derives from the placenta as well as the developing fetus). Thus women should be advised to have a positive result confirmed through diagnostic testing, preferably by amniocentesis, if they are considering a possible termination of pregnancy.
  • The better test performance, including lower invasive testing rate of NIPT-based screening should not lead to lower standards for pretest information and counseling. This is especially important in the light of the aim of providing pregnant women with meaningful options for reproductive choice. There should be specific attention paid to the information needs of women from other linguistic and cultural backgrounds or who are less health literate.
  • If NIPT is offered for a specific set of conditions (eg, trisomies 21, 18 and 13), it may not be reasonably possible to avoid additional findings, such as other chromosomal anomalies or large scale insertions or deletions. As part of pretest information, women and couples should be made aware of the possibility of such additional findings and the range of their implications. There should be a clear policy for dealing with such findings, as much as possible also taking account of pregnant women’s wishes with regard to receiving or not receiving specific information.
  • Expanding NIPT-based prenatal screening to also report on sex chromosomal abnormalities and microdeletions not only raises ethical concerns related to information and counseling challenges but also risks reversing the important reduction in invasive testing achieved with implementation of NIPT for aneuploidy, and is therefore currently not recommended.”

 

National Society of Genetic Counselors

In 2013, the National Society of Genetic Counselors (NSGC) published a position statement on NIPS of cell-free DNA in maternal plasma.  NSGC supports noninvasive cell-free DNA testing as option in women who want testing for aneuploidy. The document states that the test has been primarily validated in pregnancies considered to be at increased risk of aneuploidy, and the organization does not support routine first-tier screening in low-risk populations. In addition, the document states that test results should not be considered diagnostic, and abnormal findings should be confirmed through conventional diagnostic procedures, such as chronic villous sampling (CVS) and amniocentesis.

 

American College of Medical Genetics and Genomics

In 2013, the American College of Medical Genetics and Genomics (ACMG) published a statement on noninvasive prenatal screening for fetal aneuploidy that addresses challenges in incorporating noninvasive testing into clinical practice. Limitations identified include that chromosomal abnormalities such as unbalanced translocations, deletions and duplications, single-gene mutations, and neural tube defects cannot be detected by the new tests. Moreover, it currently takes longer to obtain test results than with maternal serum analytes. ACMG also stated that pretest and posttest counseling should be performed by trained personnel.

 

In 2016, the American College of Medical Genetics and Genomics (ACMG) published updated position statement regarding noninvasive prenatal screening for fetal aneuploidy.

 

Should noninvasive prenatal screening (NIPS) be offered to all patients including those at low or average risk?

  • ACMG recommends:
    • Informing all pregnant women that NIPS is the most sensitive screening option for traditionally screened aneuploidies (i.e. Patau, Edwards, and Down Syndromes).
    • Referring patients to a trained genetics professional when an increased risk of aneuploidy is reported after NIPS
    • Offering diagnostic testing when a positive screening test result is reported after NIPS. 

Should NIPS be used to screen for autosomal aneuploidies other than Patau, Edwards, and Down Syndromes?

  •  ACMG does not recommend:
    • NIPS to screen for autosomal aneuploidies other than those involving chromosomes 13, 18, 21. 

Should NIPS be offered to screen for sex chromosome aneuploidies?

  • ACMG recommends:
    • Informing all pregnant women, as part of pretest counseling for NIPS, of the availability of the expanded use of screening for sex chromosome aneuploidies.
    • Providers should make efforts to deter patients from selecting sex chromosome aneuploidy screening for the sole purpose of biologic sex identification in the absence of clinical indication for this information.
    • Informing patients about the causes and increased possibilities of false-positive results for sex chromosome aneuploidies as part of pretest counseling and screening for these conditions. Patients should also be informed of the potential for results of conditions that, once confirmed, may have a variable prognosis (e.g. Turner syndrome) before consenting to screening for sex chromosomes aneuploidies.
    • Referring patients to a trained genetics professional when an increased risk of sex chromosome aneuploidy is reported after NIPS.
    • Offering diagnostic testing when a positive screening test result is reported after screening for sex chromosome aneuploidies.

Should NIPS be offered for detection of copy number variation (CNV)?

  •  ACMG recommends:
    • Informing all pregnant women of the availability of the expanded use of NIPS to screen for clinically relevant:
      • Obstetric care providers should discuss with their patients the desire for prenatal screening as opposed to diagnostic testing (i.e. CVS or amniocentesis)
      • Obstetric care providers should discuss with their patients the desire for maximum fetal genomic information through prenatal screening.
      • Obstetric care providers should inform their patients of the higher likelihood of false-positive and false-negative results for these conditions as compared to results obtained when NIPS is limited to common aneuploidy screening.
      • Obstetric care providers should inform their patients of the potential for results of conditions that once confirmed may have an uncertain prognosis.
    • Referring patients to a trained genetics professional when NIPS identifies a CNV.
    • Offering diagnostic testing (CVS or amniocentesis) with CMA when NIPS identifies CNV. 
  • ACMG does not recommend:
    • NIPS to screen for genome wide CNVs. If this level of information is desired, then diagnostic testing (e.g. chorionic villous sampling or amniocentesis) followed by CMA is recommended. 

Special Considerations - multiple gestation and/or donor oocytes

  • ACMG recommends:
    • In pregnancies with  multiple gestations and/or donor oocytes, testing laboratories should be contacted regarding the validity of NIPS before it is offered to the patient as a screening option.

 

International Society for Prenatal Diagnosis

In 2015, the International Society for Prenatal Diagnosis published a position statement on prenatal diagnosis of chromosomal abnormalities, an update of their 2013 statement.34,35 (Note that a number of the authors of the 2015 report had financial links to industry.) Following is the summary of recommendations:

  1. High sensitivities and specificities are potentially achievable with cfDNA [cell-free DNA] screening for some fetal aneuploidies, notably trisomy 21
  2. Definitive diagnosis of Down syndrome and other fetal chromosome abnormalities can only be achieved through testing on cells obtained by amniocentesis or CVS
  3. The use of maternal age alone to assess fetal Down syndrome risk in pregnant women is not recommended.
  4. A combination of ultrasound NT measurement and maternal serum markers in the first trimester should be available to women who want an early risk assessment and for whom cfDNA screening cannot be provided.
  5. A four-marker serum test should be available to women who first attend for their prenatal care after 13 weeks 6 days of pregnancy and where cfDNA screening cannot be provided.
  6. Protocols that combine first trimester and second trimester conventional markers are valid.
  7. Second trimester ultrasound can be a useful adjunct to conventional aneuploidy screening protocols.
  8. When cfDNA screening is extended to microdeletion and microduplication syndromes or rare trisomies the testing should be limited to clinically significant disorders or well defined severe conditions. There should be defined estimates for the detection rates, false-positive rates, and information about the clinical significance of a positive test for each disorder being screened.

 

Prior Approval:

 

Not applicable

 

Policy:

High - Risk Singleton Pregnancies

Noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma (including but not limited to the following: MarterniT21, MaterniT21 Plus, Verifi Prenatal Test, Harmony Prenatal Test, Panorama Prenatal Test, QNatal Advanced and InformSeqSM) for fetal aneuploidy (trisomy 13, 18 and 21) is considered medically necessary in women with high – risk singleton pregnancies meeting the following criteria:

  • Maternal age 35 years or older at delivery; or

  • Fetal ultrasound findings indicate an increased risk of aneuploidy*; or

  • History of prior pregnancy with aneuploidy (trisomy); or 

  • Positive test result for aneuploidy, including first trimester, sequential, or integrated screen, or a quadruple screen; or

  • Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21

Note: See Policy Guidelines for ultrasound findings criteria indicating increased risk for aneuploidy.* 

 

Concurrent noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for trisomy 13 and/or 18 may be considered medically necessary in women who are eligible and undergoing noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for trisomy 21.

 

Noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for trisomy 13 and/or 18, other than in the situation specified above, is considered investigational because the safety and/or effectiveness cannot be established based on review of available peer reviewed medical literature.

 

Average/Low Risk Singleton, Twin and Multiple Pregnancies

Noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for fetal aneuploidy (trisomy 13, 18, 21) is considered investigational in women with average/low risk singleton pregnancies, twin or multiple pregnancies. 

 

Cell-free fetal DNA testing for aneuploidy has been proven to be accurate and reproducible in the population of women with pregnancies at high risk for aneuploidy. However further well-designed clinical trials are needed to further define the role of this testing in routine pregnancy management as compared to the current standard evaluation of serum biomarkers with or without ultrasonic measurement of nuchal translucency, followed by invasive testing as indicated. Currently the quality and quantity of evidence does not support the use of cell-free fetal DNA testing for singleton pregnancies at average/low risk for aneuploidy. Therefore the use of cell-free fetal DNA testing average/low risk singleton pregnancies is considered investigational.

 

The data regarding the performance of NPIT using cell-free DNA screening in twin and multiple gestations are limited. Although preliminary findings suggest that this screening is accurate, larger prospective studies and published data are needed before this method can be recommended for twin or multiple gestations. Cell-free DNA is not recommended for women with twin gestations and there is no available data on higher-order multiples. Therefore, the evidence is insufficient to determine the effects of this technology on net health outcomes and is considered investigational.

 

Fetal Sex Chromosome Aneuploidies

Noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for fetal sex chromosome aneuploidies is considered investigational because the safety and/or effectiveness cannot be established based on review of available peer reviewed medical literature. 

 

Microdeletions

Noninvasive prenatal testing (NPIT) using cell free fetal DNA of maternal plasma for microdeletions is considered investigational because the safety and/or effectiveness cannot be established based on review of available peer reviewed medical literature.

 

Policy Guideines

*Ultrasound Findings:

Trisomy 21 (Down syndrome) — Approximately one-third of fetuses with trisomy 21 have one or more sonographically detectable structural malformations (major or minor) in the following systems:

  • Cardiovascular, especially endocardial cushion defects and ventricular septal defects
  • Central nervous system (e.g., mild ventriculomegaly)
  • Gastrointestinal system (e.g., duodenal atresia [after 22 weeks]
  • Other

Trisomy 18 — After Down syndrome, trisomy 18 is the second most common autosomal trisomy detected in the second trimester; it is almost always lethal in early childhood). Sonographic abnormalities include:

  • Limb abnormalities (e.g., upper limb reduction, clenched hands with overlapping index finger, clubbed feet, rocker bottom feet)
  • Nuchal thickening or cystic hygroma
  • Choroid plexus cyst(s)
  • Other

Trisomy 13— Trisomy 13 is rare (incidence 1/5,000 to 1/20,000 births) and associated with more severe structural malformations than trisomy 21 or 18. It is sonographically detectable in >90 percent of cases due to the presence of multiple, severe structural malformations, including:

  • Alobar holoprosencephaly
  • Severe midline facial abnormalities (e.g., cyclopia, midline facial clefts, anophthalmia, hypoplastic nose)
  • Polycystic kidneys
  • Other

Definitions

Average/Low Risk Pregnancy: No active complications and that there are no maternal or fetal factors that place the pregnancy at increased risk for complications.

 

Aneuploidy: an abnormal number of chromosomes in the cell. Except for red blood cells and the sperm and egg cells, every cell in the human body has 23 pairs of chromosomes (for a total of 46).

 

Translocation: A translocation occurs when a segment of genetic material from one chromosome becomes linked to another chromosome:

  • A balanced translocation results in no excess or deficit in genetic material and causes no health difficulties.
  • An unbalanced translocation occurs when a child inherits a chromosome with an excess or deficit of genetic material from a parent with a balanced translocation.
  • Robertsonian translocations can occur in the five acrocentric chromosome pairs (numbers 13, 14, 15, 21, and 22). These are the chromosomes that have the centromere near the end, resulting in one chromosomal arm being much longer than the other. If a Robertsonian translocation occurs in one of these chromosomes, the chromosome breaks at the centromere and the long arms fuse to form a single chromosome with a single centromere. The short arms may also form a reciprocal product that usually contains nonessential genes and are usually lost within a few cell divisions. The child of someone with a balanced Robertsonian translocation may either be normal (carrying the fusion chromosome) or they may inherit an acrocentric chromosome with a missing or extra long arm. This results in multiple malformations including trisomy 13 (Patau syndrome) and trisomy 21 (Down syndrome).

Trisomy: three copies of a chromosome are present instead of the usual pairs. Syndromes associated with trisomies include:

  • Down syndrome is caused by a trisomy of chromosome 21. Down syndrome is the most common single cause of birth defects, occurring in 1 in 800 live births. Down syndrome is associated with a variety of clinical abnormalities including mild-to-moderate mental retardation, cardiac defects, thyroid problems, seizures, hearing loss, and duodenal atresia (absence or closure of the first section of the small intestine).
  • Edwards syndrome is caused by a trisomy of chromosome 18, which causes major physical abnormalities and severe mental retardation. Trisomy 18 occurs in approximately one in 5000 live births.
  • Patau syndrome is caused by a trisomy of chromosome 13. Trisomy 13 occurs in approximately one in 10,000 live births and causes neurological, heart and kidney defects.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD diagnosis codes.

  • 81420  Fetal chromosomal aneuploidy (eg, trisomy 21, monosomy X) genomic sequencing analysis panel, circulating cell free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18, and 21
  • 81422  Fetal chromosomal microdeletion(s) genomic sequence analysis (e.g. DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free NDA in maternal blood 
  • 81507  Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma algorithm reported as a risk score for each trisomy
  • 0009M  Fetal aneuploidy (trisomy 21 and 18) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as risk score for each trisomy
  • 81479  Unlisted molecular pathology procedures
  • 81599  Unlisted multi-analyte assay with algorithmic analysis

 

Selected References:

  • Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. Apr 15 1983;249(15):2034-2038. PMID 6220164
  • American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. Jan 2007;109(1):217-227. PMID 17197615
  • Ashoor G, Syngelaki A, Poon LC, et al. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks'gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol. Jan 2013;41(1):26-32. PMID 23108725
  • Blue Cross Blue Shield Association Technology Evaluation Center (BCBSA TEC). Sequencing-based tests to determine fetal down syndrome (trisomy 21) from maternal plasma DNA. TEC Assessment Program. 2013;27(10).
  • Blue Cross Blue Shield Association Technology Evaluation Center (BCBSA TEC). Noninvasive maternal plasma sequencing-based screening for fetal aneuploides other than trisomy 21. 2014;In Press.
  • Gil MM, Akolekar R, Quezada MS, et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther. Feb 8 2014;35(3):156-173. PMID 24513694
  • Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. Mar 2012;14(3):296-305. PMID 22281937
  • Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. Nov 2011;13(11):913-920. PMID 22005709
  • Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. Mar 2011;204(3):205 e201-211. PMID 21310373
  • Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNAsequencing. Obstet Gynecol. May 2012;119(5):890-901. PMID 22362253
  • Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. Jul 2011;57(7):1042-1049. PMID 21519036
  • Norton ME, Brar H, Weiss J, et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. Aug 2012;207(2):137 e131-138. PMID 22742782
  • Ashoor G, Syngelaki A, Wagner M, et al. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol. Apr 2012;206(4):322 e321-325. PMID 22464073
  • Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. Apr 2012;206(4):319 e311-319. PMID 2246407
  • Nicolaides KH, Syngelaki A, Gil M, et al. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. Jun 2013;33(6):575-579. PMID 23613152
  • Porreco RP, Garite TJ, Maurel K, et al. Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. Am J Obstet Gynecol. Mar 19 2014. PMID 24657131
  • Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. Apr 23 2015;372(17):1589-1597. PMID 25830321
  • Zhang H, Gao Y, Jiang F, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol. May 2015;45(5):530-538. PMID 25598039
  • Pergament E, Cuckle H, Zimmermann B, et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. Aug 2014;124(2 Pt 1):210-218. PMID 25004354
  • Canick JA, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. May 14 2012:1-5. PMID 22585317
  • Ohno M, Caughey A. The role of noninvasive prenatal testing as a diagnostic versus a screening tool--a costeffectiveness analysis. Prenat Diagn. Jul 2013;33(7):630-635. PMID 23674316
  • Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. Mar 2015;212(3):332 e331-339. PMID 25479548
  • Gross SJ, Stosic M, McDonald-McGinn DM, et al. Clinical Experience with Single-Nucleotide Polymorphism-Based Noninvasive Prenatal Screening for 22q11.2 Deletion Syndrome. Ultrasound Obstet Gynecol. Sep 23 2015. PMID 26396068
  • Helgeson J, Wardrop J, Boomer T, et al. Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing. Prenat Diagn. Oct 2015;35(10):999-1004. PMID 26088833
  • Zhao C, Tynan J, Ehrich M, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem. Apr 2015;61(4):608-616. PMID 25710461
  • Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. Obstet Gynecol. Jun 29 2015. PMID 26114726
  • American College of Obstetricians and Gynecologists (ACOG). Commitee Opinion: Noninvasive Prenatal Testing for Fetal Aneuploidy 2012.
  • Dondorp W, de Wert G, Bombard Y, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations. Eur J Hum Genet. Apr 1 2015. PMID 25828867
  • Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: theposition of the National Society of Genetic Counselors. J Genet Couns. Jun 2013;22(3):291-295. PMID 23334531
  • Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med. May 2013;15(5):395-398. PMID 23558255
  • Benn P, Borrell A, Chiu RW, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. Aug 2015;35(8):725-734. PMID 25970088
  • Benn P, Borell A, Chiu R, et al. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. Jul 2013;33(7):622-629. PMID 23616385
  • UpToDate Prenatal Screening for Down Syndrome Using Cell-Free DNA. Glenn E. Palomaki, PhD, Geralyn M Messerlian, PhD, Jacquelyn V Halliday, MS, Topic last updated January 4, 2016.
  • UpToDate. Prenatal Screening for Common Aneuploidies Using Cell Free DNA. Gleen E. Palomaki PhD, Geralyn M. Messerlian PhD, Jacquelyn V. Halliday M.S. Topic last updated January 10, 2017.
  • UpToDate. Down Syndrome Overview of Prenatal Screening. Geralyn M. Messerlian PhD, Gleen E. Palomaki PhD. Topic last updated April 28, 2016.
  • Gregg A, Skotko B, Benkendorf J, et. al. Noninvasive prenatal screening for fetal aneuploidy 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genetics in Medicine online publication July 28, 2016 doi:10.1038/gim.2016.97 
  • Ashoor G, Syngelaki A, Poon LC, et al. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol. Jan 2013;41(1):26-32. PMID 23108725 
  • Gil MM, Akolekar R, Quezada MS, et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther. Feb 8 2014;35(3):156-173. PMID 24513694
  • Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. Jul 2011;57(7):1042-1049. PMID 21519036
  • Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. Apr 2012;206(4):319 e311-319. PMID 22464072
  • Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. Apr 23 2015;372(17):1589-1597. PMID 25830321
  • Zhang H, Gao Y, Jiang F, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol. May 2015;45(5):530-538. PMID 25598039
  • Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. Mar 2015;212(3):332 e331-339. PMID 25479548
  • Gross SJ, Stosic M, McDonald-McGinn DM, et al. Clinical Experience with Single-Nucleotide Polymorphism-Based Noninvasive Prenatal Screening for 22q11.2 Deletion Syndrome. Ultrasound Obstet Gynecol. Sep 23 2015. PMID 26396068
  • Helgeson J, Wardrop J, Boomer T, et al. Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing. Prenat Diagn. Oct 2015;35(10):999-1004. PMID 26088833
  • Zhao C, Tynan J, Ehrich M, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem. Apr 2015;61(4):608-616. PMID 25710461 

 

Policy History:

  • February 2017 - Annual Review, Policy Revised
  • February 2016 - New medical policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.