BlueCross and BlueShield of Montana Medical Policy/Codes
Prenatal and Preconception Genetic Tests
Chapter: Genetic Testing
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

A chromosome is an organized package of DNA found in the nucleus of the cell. Humans have 23 pairs of chromosomes--22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, XX (female) or XY (male). Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father. (26, 27)

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. (1)

Combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy are used to screen for fetal aneuploidy, 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. Massively parallel sequencing (MPS; also known as next generation or “next-gen” sequencing) can be used to design assays for prenatal diagnosis of chromosomal trisomy. 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. Alternatively, chromosome-targeted sequencing can be used, which obviates the need for mapping to the reference human genome.

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. Additionally, in a euploid individual with normal chromosome numbers (e.g., the woman from whom the plasma sample was taken), the proportional contribution of DNA sequences per chromosome correlates with the relative size of each chromosome in the human genome. Any detectable difference from the euploid mean for each chromosome of interest is determined for the sample. A predetermined cutoff identifies samples that have abnormal chromosome numbers.

Thus, 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:

  • In October 2011, Sequenom (San Diego, CA) introduced its MaterniT21™ test to test for trisomy 21, 18 and 13. The test is offered through the company’s CLIA laboratory, the Sequenom Center for Molecular Medicine.
  • In March 2012, Verinata Health (Redwood, CA) launched its verifi® prenatal test for trisomy 21, 18, and 13.
  • In May 2012, Ariosa Diagnostics (San Jose, CA) (formerly Aria) launched its Harmony™ test for trisomy 21 and 18, which is available from Integrated Genetics, a division of LabCorp.
  • Natera (San Carlos, CA) plans to introduce its prenatal test for detecting aneuploidy in late 2012.

A gene is the basic physical and functional unit of heredity. Genes are made up of DNA, and in humans genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project (National Institutes of Health) has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features. (22)

Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition. (23)

Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however. (23)

Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. (24)

Patterns Of Inheritance*

Inheritance Pattern

Description

Examples

Autosomal dominant

One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.

Huntington Disease, Neurofibromatosis type 1

Autosomal recessive

Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.

Cystic fibrosis, Sickle cell anemia

X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women). Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

Fragile-X syndrome

X-linked recessive

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

Hemophilia, Fabry disease

Codominant

In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

Alpha-1 antitrypsin deficiency, ABO blood group

Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial mutations to their children. Disorders resulting from mutations in mitochondrial DNA can appear in every generation of a family and can affect both males and females, but fathers do not pass these disorders to their children.

Leber hereditary optic neuropathy

Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer

Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next.

Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

* Genetics Home Reference, www.nih.gov (25)
Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Fetal Aneuploidy (Trisomy 21, 18 or 13)

Nucleic acid sequencing-based testing of maternal plasma for fetal aneuploidy (trisomy 21, 18 or 13) may be considered medically necessary in women with high-risk singleton pregnancies, defined as:

  1. Maternal age 35 years or older at delivery; OR
  2. Fetal ultrasonographic findings indicating increased risk of aneuploidy; OR
  3. History of previous pregnancy with a trisomy; OR
  4. Standard serum screening test positive for aneuploidy; OR
  5. Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21.

Nucleic acid sequencing-based testing of maternal plasma for fetal aneuploidy (trisomy 21, 18 or 13) is considered not medically necessary in women with singleton pregnancies that are not high-risk.

Nucleic acid sequencing-based testing of maternal plasma for fetal aneuploidy (trisomy 21, 18 or 13) is considered experimental, investigational and unproven in women with twin or multiple pregnancies.

Other Prenatal and Preconception Genetic Tests

Other prenatal and preconception genetic tests (*see list of tests below) may be considered medically necessary when done to determine carrier status and/or to guide reproductive decisions, and parents or prospective parents meet both A) Family History Criteria, and  B) Genetic Test Criteria:

A) Family History Criteria—At least one of the parents/prospective parents must:

  1. Have family history of a first-, second-, or third-degree relative** who has an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance; OR
  2. Have family history of a first-degree relative who has an affected child with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance; OR
  3. Have high risk of a genetic disorder with a late onset; OR
  4. Have an affected child with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance; OR
  5. Be member(s) of an ethnic group with a high risk of a specific genetic disorder with an autosomal recessive pattern of inheritance (e.g., Ashkenazi Jewish descent). NOTE: Identification of family history and/or ethnic origin should be attempted; one Jewish grandparent is enough to offer testing; AND

B) Genetic Test Criteria:

  1. The genetic disorder is associated with a potentially severe disability or has a lethal natural course; OR
  2. A biochemical or other test is identified but the results are indeterminate, or the genetic disorder cannot be identified through biochemical or other testing.

*When the above criteria are met, the following genetic tests may be considered medically necessary:

  1. Bloom syndrome (BLM);
  2. Canavan disease (ASPA, aspartoacylase A);
  3. Familial dysautonomia (IKBKAP);
  4. Fanconi anemia group C (FANCC, FANCD);
  5. Fetal skeletal dysplasias (FGFR3);
  6. Fragile X syndrome (FMR1);
  7. Gaucher's disease (GBA, acid beta glucosidase);
  8. Hemoglobulinopathies (HBA1, HBA2);
  9. Mucolipidosis IV (MCOLN1, mucolipin 1);
  10. Nieman Pick Disease Type A (SMPD1);
  11. Spinal muscular atrophy (SMN1, SMN2);
  12. Tay-Sach's disease (HEXA, hexosaminidase A).

Cystic Fibrosis

Prenatal or preconception genetic testing of a parent or prospective parent to determine carrier status of common variants of cystic fibrosis (CPT® 81220) may be considered medically necessary.

Prenatal or preconception genetic testing of a parent or prospective parent to determine carrier status of cystic fibrosis for known familial variant (common variant) (CPT® 81221) may be considered medically necessary when there is history of such variant in a first-, second-, or third-degree relative.

When the above criteria are not met, prenatal and preconception genetic tests done to determine carrier status and/or to guide reproductive decisions are considered experimental, investigational and unproven.

**  DEFINITIONS:

  1. First degree relatives include parents, siblings and offspring;
  2. Second degree relatives include half-brothers/sisters, aunts/uncles, grandparents, grandchildren and nieces/nephews;
  3. Third degree relatives include first cousins, great-aunts/uncles, great-grandchildren and great grandparents.

Rationale

Fetal Aneuploidy (Trisomy 21, 18 or 13)

Literature Review

The review of aneuploidy is based on a 2012 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment and also includes a search of the MEDLINE database and national practice guidelines/position statements through November 2012. The Assessment focused on detection of trisomy 21/Down syndrome because the majority of published data was concentrated on this trisomy, large numbers of cases were included in several publications, and all companies had published data regarding the detection of trisomy 21. The Assessment also reviewed the available data for detection of trisomy 18 and 13. The TEC Assessment and the policy both limit their scope to the evaluation of tests that are available in the United States.

Assessment of a diagnostic technology such as maternal plasma DNA sequencing tests typically focuses on 3 parameters: 1) analytic validity; 2) clinical validity (i.e., sensitivity and specificity) in appropriate populations of patients; and 3) demonstration that the diagnostic information can be used to improve patient health outcomes (clinical utility). The evidence on these 3 questions, as summarized in the TEC assessment, is described below.

What is the analytic validity of the available maternal plasma DNA sequencing-based tests?

No studies were identified that provided direct evidence on analytic validity. Each of the commercially available tests uses massively parallel sequencing (MPS; also called next generation sequencing), 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 FDA held an exploratory, public meeting on the topic of MPS, in preparation for an eventual goal of developing “a transparent evidence-based regulatory pathway for evaluating medical devices/products based on NGS [next generation sequencing] that would assure safety and effectiveness of devices marketed for clinical diagnostics.” (3) The discussion pointed out the differences among manufacturers’ sequencing platforms and the diversity of applications, making it difficult to generate specific regulatory phases and metrics. 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 for fetal trisomy 21 has developed a specific procedure for its private, CLIA-licensed laboratory where all testing takes place.

Conclusions

Although all currently available commercially available tests use MPS, actual performance and interpretive procedures vary considerably. Clinical sequencing in general is not standardized or regulated by the FDA 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.

What is the clinical validity of the available maternal plasma DNA sequencing-based tests for trisomy 21 compared to the gold standard of karyotype analysis?

Eight studies were included that provided data on the sensitivity and specificity of the final, clinical nucleic acid sequencing-based assay of maternal plasma for trisomy 21 in singleton pregnancies. (4-12) Tests from 3 commercial sources were identified: 2 studies used the Sequenom test, 2 studies used the Verinata test and 4 studies used the Ariosa Diagnostics test. Studies are underway by a fourth manufacturer, Natera. Six studies were entirely prospective, and 2 retrospectively evaluated archived samples. Seven of 8 studies were industry-funded; in the 8th, testing was provided gratis.

With one exception, the enrolled study populations included women at increased risk due to increased age and/or standard screening results or because they were already scheduled for amniocentesis or chorionic villous sampling (CVS). Nicolaides and colleagues evaluated archived samples from women attending their routine first pregnancy visit at 11-14 weeks’ gestation. (9) Studies generally included women at a wide range of gestational ages (e.g., 8-36 weeks or 11-20 weeks) spanning first and second trimesters.

The approach to analysis varied. Some studies analyzed samples from all enrolled women and others analyzed samples from all women with pregnancies known to have a trisomy syndrome and selected controls (i.e., nested case-control analysis within a cohort). All studies but one evaluated the results of maternal fetal DNA testing in comparison to the gold standards of karyotyping or, in individual cases when a sample did not allow karyotyping, fluorescence in situ hybridization (FISH) for specific trisomies. Because they were evaluating an average-risk population, Nicolaides et al. had karyotyping results for only a small percentage of women in their study; for the rest of the enrollees, chromosomal status was determined by phenotype at birth obtained from medical records.

Sample sizes of the studies ranged from 119 to 1,988 patients. These numbers represent the samples analyzed, including euploid controls; in some studies, samples were drawn from larger available cohorts of collected samples. All studies included testing for trisomy 21. Eight studies additionally tested for trisomy 18 and 4 studies additionally tested for trisomy 13. There were fewer cases of T18 (range: 3-59) and T13 (range: 1-14) per study compared to T21. Four studies had 50 or more cases of T21, and one study, Palomaki et al. 2011, (5) had 212 cases.

The sensitivity and specificity estimates of testing for trisomy 21 in singleton pregnancies were uniformly high. The sensitivity ranged from 99.1% to 100%, and the specificity ranged from 99.7% to 100%.

Detection of trisomy 21 in twin pregnancies was systematically evaluated in only one study, published in 2012 by Canick and colleagues; the study used the Sequenom test. (13) All 7 cases of twin pregnancies with Down syndrome were correctly classified. Five of these were discordant, where one twin had T21 aneuploidy and the other did not; 2 were concordant where both twins had T21 aneuploidy.

Conclusions

Data from 8 studies consistently reported a very high sensitivity and specificity of maternal plasma DNA sequencing-based tests for detecting trisomy 21 in high-risk women with singleton pregnancies. Only one of these studies included women at average-risk of trisomy 21. Thus, there is sufficient evidence that the tests are accurate when used in women with high-risk pregnancies, but the evidence on women with average-risk pregnancies is insufficient. For women with multiple pregnancies, there is insufficient evidence to draw conclusions about the diagnostic accuracy of these tests for detecting trisomy 21.

What is the clinical utility of the available maternal plasma DNA sequencing-based tests for aneuploidy?

No comparative studies were evaluated that compared health outcomes in patients managed using the maternal plasma DNA tests compared to standard screening tests.

As part of the 2012 TEC Assessment, a decision model was constructed to model health outcomes of sequencing-based testing for trisomy 21 compared to standard testing. The primary health outcomes of interest included the number of cases of aneuploidy correctly identified, the number of cases missed, the number of invasive procedures potentially avoided (i.e., 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 results of the decision model in the TEC Assessment, 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 U.S. per year (14) 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 3,976 of 4,200 (94.7%) trisomy 21/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 7,504 and the number of miscarriages reduced to 28, while the cases of Down syndrome detected would increase to 4,144 of 4,200 (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 4,116, miscarriages would remain at 28, but fewer Down syndrome cases would be detected (3,948 of 4,200, 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.

At least two decision models have also been presented in industry-funded publications, each using a different commercially available test and published estimates of sensitivity and specificity. Findings of both these models are similar to the TEC Assessment model in that detection of T21 is increased and miscarriage rates are decreased using sequencing-based testing compared to standard screening. Both of the studies specifically model use of sequencing-based tests offered to women who have had a positive standard screening test.

Garfield and Armstrong published a study modeling use of the Verinata test. (15) In the model, women were eligible for screening following a positive first-trimester or second-trimester screening test or following a second-trimester ultrasound. The model assumed that 71% of women at average risk and 80% of women at high risk would choose the test. In a theoretical population of 100,000 pregnancies, the detection rate of T21 increased from 148 with standard testing to 170 with verifi® testing. In addition, the number of miscarriages associated with invasive testing (assumed to be 0.5% for amniocentesis and 1% with CVS) was reduced from 60 to 20.

Palomaki and colleagues modeled use of the Sequenom sequencing-based test offered to women after a positive screening test, with invasive testing offered only in the case of a positive sequencing-based test. (4) As in the TEC Assessment, they assumed 4.25 million births in the U.S. per year, with two-thirds of these receiving standard screening. The model assumed a 99% detection rate, 0.5% false positive rate, and 0.9% failure rate for sequencing-based testing. Compared to the highest performing standard screening test, the addition of sequencing-based screening would increase the Down syndrome detection rate from 4,450 to 4,702 and decrease the number of miscarriages associated with invasive testing from 350 to 34.

It is important to note that all of the above models include confirmatory invasive testing for positive screening tests. Sequencing-based testing without confirmatory testing carries the risk of misidentifying normal pregnancies as positive for trisomy. Due to the small but finite false positive rate, together with the low baseline prevalence of trisomy in all populations, a substantial percent of positive results on sequencing tests could be false positive results.

Conclusions

There is no published direct evidence that managing patients using sequencing-based testing improves health outcomes compared to standard screening. 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 a large decrease in the number of invasive tests and associated miscarriages.

Ongoing Clinical Trials

Prenatal Non-invasive Aneuploidy Test Utilizing SNPs [single nucleotide polymorphism] Trial (PreNATUS) (NCT01545674) (16): This is a prospective, blinded study evaluating the diagnostic accuracy of the Natera test for diagnosing aneuploidies (chromosomes 13, 18, 21) and sex aneuploidy (X and Y). It includes women with singleton pregnancies at high or moderate risk for trisomy who were planning on undergoing invasive testing. Gestational age of the fetus is between 8 weeks 0 days and 23 weeks 6 days. The estimated enrollment is 1,000 participants and the expected date of study completion is December 2012.

Non-invasive Chromosomal Examination of Trisomy study (NEXT) (NCT01511458) (17): This is a prospective blinded case-control study comparing the Aria test for trisomy 21 with standard first-trimester prenatal screening (maternal serum testing and nuchal translucency). Cases will consist of patients with trisomy 21 pregnancies confirmed by genetic testing, and controls will consist of patients without trisomy 21 pregnancies, as confirmed by genetic testing or live birth. The study is sponsored by Aria Diagnostics. The estimated enrollment is 25,000 individuals. The expected date of study completion is July 2013.

Comparison of Aneuploidy Risk Evaluations (CARE) (NCT01663350) (18): This prospective observational study is comparing diagnostic accuracy of the Verinata Health prenatal aneuploidy test and conventional non-invasive screening. The study will include all risk levels. Entry criteria include adult women with clinically confirmed pregnancy at gestational age of at least 8 weeks who plan to complete or who have completed prenatal serum screening. The study is sponsored by Verinata Health; expected enrollment is 3,000 women. The expected date of study completion is not available.

Clinical Evaluation of the SEQureDx T21 Test in Low Risk Pregnancies (NCT01597063) (19): This is a prospective study and includes pregnant women between 10-22 weeks’ gestation who are at low risk for trisomy 21 aneuploidy (i.e., no positive prenatal screening tests, and no personal or family history of Down syndrome). Blood samples will be collected at a scheduled prenatal care visit and analyzed with the SEQureDX T21 test; pregnancies will be followed until the birth outcome is recorded. The study is sponsored by Sequenom; estimated enrollment is 1,600. The expected date of study completion is August 2013.

Practice Guidelines and Position Statements

In November 2012, the American College of Obstetricians and Gynecologists (ACOG) released a committee opinion on noninvasive testing for fetal aneuploidy. (20) The Committee Opinion was issued jointly with the Society for Maternal-Fetal Medicine Publications Committee. ACOG recommended that maternal plasma DNA testing be offered to patients at increased risk of fetal aneuploidy. They did not recommend that the test be offered to women who are not at high risk or women with multiple gestations. ACOG further recommended that women be counseled prior to testing about the limitations of the test and recommended confirmation of positive findings with CVS or amniocentesis. The document noted that the content reflected emerging clinical and scientific advances and is subject to change as additional information becomes available. The Committee Opinion did not include an explicit review of the literature.

The International Society for Prenatal Diagnosis (ISPD) published a rapid response statement on October 24, 2011 regarding non-invasive tests based on the presence of cell-free fetal nucleic acids in maternal plasma. (21) ISPD considers these tests to be advanced screening tests, requiring confirmation through invasive testing. They further suggest that trials are needed in low-risk populations and in sub-populations such as twin pregnancies and in vitro fertilization donor pregnancies.

The National Society of Genetic Counselors (NSGC) published a position statement on their website regarding noninvasive prenatal testing of cell-free DNA in maternal plasma. (1) The NSGC supports this testing “as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities.” They recommend that the test be offered in the context of informed consent and that patients whose results are abnormal be offered standard confirmatory (i.e., invasive) testing.

Summary

Published studies from all three commercially available tests have consistently demonstrated very high sensitivity and specificity for detecting Down syndrome (trisomy 21) in singleton pregnancies. Seven of the 8 published studies included only women at high-risk of trisomy 21. Direct evidence of clinical utility is not available. A 2012 TEC Assessment modeled comparative outcomes based on the published data on test performance, published estimates of standard screening performance, patient uptake of confirmatory testing, and miscarriage rates associated with invasive procedures. For each comparison and in each risk population, sequencing-based testing improved outcomes, i.e., increased the rate of Down syndrome detection and reduced the number of invasive procedures and procedure-related miscarriages. In the modeling, the negative predictive value of testing approached 100% across the range of aneuploidy risk, while the positive predictive value varied widely according to baseline risk. The variable positive predictive value highlights the possibility of a false positive finding and thus testing using karyotyping is necessary to confirm a positive result.

Based on the available evidence, including modeling in the TEC assessment, as well as recommendations from ACOG, nucleic acid sequencing-based testing for trisomy 21 may be considered medically necessary in women with high-risk singleton pregnancies who meet criteria and not medically necessary in women with average-risk singleton pregnancies.

Other Prenatal and Preconception Genetic Tests

Both the American College of Obstetrics and Gynecology (ACOG) and the American College of Medical Genetic (ACMG) have published guidelines that recommend prenatal and preconception genetic testing for Canavan disease, cystic fibrosis, familial dysautonomia, Tay-Sachs, Fanconi anemia group C, Bloom disease, Niemann-Pick disease type A, mucolipidosis IV, skeletal dysplasias, Fragile X, and Gaucher disease. In addition, the ACMG recommends prenatal and preconception testing for spinal muscular atrophy. (28-37)

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

V23.81, V26.33, V28.3

ICD-10 Codes

009.51, Z31.430-Z31.438, Z31.440-Z231.448, Z36

Procedural Codes: 81200, 81209, 81220, 81221, 81222, 81223, 81224, 81242, 81243, 81244, 81251, 81255, 81257, 81260, 81290, 81330, 81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479, 81507, 81599, 0005M, S3845, S3846, S3849, S3850
References
  1. National Society of Genetic Counselors (NSGC). Noninvasive prenatal testing/ noninvasive prenatal diagnosis (NIPT/NIPD) Available online at www.nsgc.org (accessed October, 2012).
  2. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007; 109(1):217-27.
  3. Food and Drug Adminstration (FDA). Ultra High Throughput Sequencing for Clinical Diagnostic Applications - Approaches to Assess Analytical Validity, June 23, 2011. Available online at <www.fda.gov> (accessed October, 2012).
  4. 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 2012; 14(3):296-305.
  5. 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 2011; 13(11):913-20.
  6. 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 2011; 204(3):205 e1-11.
  7. Bianchi DW, Platt LD, Goldberg JD et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012; 119(5):890-901.
  8. 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 2011; 57(7):1042-9.
  9. Nicolaides KH, Syngelaki A, Ashoor G et al. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012; 207(5):374.e1-6.
  10. 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 2012; 207(2):137.e1-8.
  11. 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 2012; 206(4):322.e1-5.
  12. 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 2012; 206(4):319.e1-9.
  13. 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 2012; 32(8):730-45.
  14. Centers for Disease Control (CDC). Vital Statistics Online: Birth Data. Available online at www.cdc.gov (accessed October, 2012).
  15. Garfield SS, Armstrong SO. Clinical and cost consequences of incorporating a novel non-invasive prenatal test into the diagnostic pathway for fetal trisomies. Journal of Managed Care Medicine 2012; 15(2):34-41.
  16. Sponsored by Natera Inc. Prenatal Non-invasive Aneuploidy Test Utilizing SNPs Trial (PreNATUS) (NCT01545674). Available online at www.clinicaltrials.gov (accessed October, 2012).
  17. Sponsored by Aria Diagnostics Inc. Non-invasive Chromosomal Examination of Trisomy Study (NEXT) (NCT01511458). Available online at www.clinicaltrials.gov (accessed October, 2012).
  18. Sponsored by Verinata Health, Inc. Comparison of Aneuploidy Risk Evaluations (CARE) (NCT01663350). Available online at www.clinicaltrials.gov (accessed October, 2012).
  19. Sponsored by Sequenom Inc. Clinical Evaluation of the SEQureDx T21 Test in Low Risk Pregnancies (NCT01597063). Available online at www.clinicaltrials.gov (accessed October, 2012).
  20. American College of Obstetricians and Gynecologists (ACOG). Commitee Opinion: Noninvasive Prenatal Testing for Fetal Aneuploidy. 2012. Available online at www.acog.org (accessed December, 2012).
  21. The International Society for Prenatal Diagnosis (ISPD). Prenatal Detection of Down Syndrome using Massively Parallel Sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011. Available online at www.ispdhome.org (accessed October, 2012).
  22. Inheriting Genetic Conditions (reprinted from Genetics Home Reference) US National Library of Medicine, National Institutes of Health, Department of Health and Human Services. March 25, 2013; pg 12. Available at ghr.nlm.nih.gov (accessed March 2013)
  23. Inheriting Genetic Conditions (reprinted from Genetics Home Reference) US National Library of Medicine, National Institutes of Health, Department of Health and Human Services. March 25, 2013; :pg 117-118. Available at ghr.nlm.nih.gov (accessed March 2013)
  24. Inheriting Genetic Conditions (reprinted from Genetics Home Reference) US National Library of Medicine, National Institutes of Health, Department of Health and Human Services. March 25, 2013; pg 101. Available at ghr.nlm.nih.gov (accessed March 2013)
  25. Inheriting Genetic Conditions (reprinted from Genetics Home Reference) US National Library of Medicine, National Institutes of Health, Department of Health and Human Services. March 25, 2013; pg 81-82. Available at ghr.nlm.nih.gov (accessed March 2013)
  26. Basics of Chromosomes. GeneEd—Genetics, Education, Discovery.  www.geneed.nlm.nih.gov (accessed March 2013).
  27. Genetic Conditions—An Overview. Produced by the Centre for Genetics Education 2010. Available at www.genetics.edu.au (accessed March 2013).
  28. American College of Obstetricians and Gynecologists (ACOG) committee opinion No. 423: spinal muscular atrophy. ACOG Committee on Genetics. Obstet Gynecol. 2009 May; 113(5):1194-6.
  29. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 78: Hemoglobulinopathies in pregnancy. Clinical Management Guidelines for Obstetricians-Gynecologists. January 2007; 78:968-976.
  30. American College of Obstetricians and Gynecologists (ACOG) committee opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. ACOG Committee on Genetics. October 2009; 442: 280-283.
  31. American College of Obstetricians and Gynecologists (ACOG) committee opinion No. 338: Screening for Fragile X syndrome. June 2006; 338: 265-267.
  32. American College of Obstetricians and Gynecologists (ACOG) committee opinion No. 486: Update on carrier screening for cystic fibrosis. April 2011; 486: 1-4.
  33. American College of Medical Genetics (ACMG). Fragile X syndrome: diagnostic and carrier testing. October 2005; 7(8):584-587.
  34. American College of Medical Genetics (ACMG). Carrier screening in individuals of Ashkenazi Jewish descent. January 2008; 10(1):54-56.
  35. American College of Medical Genetics (ACMG). Carrier screening for spinal muscular atrophy. November 2008; 10(11): 840-842.
  36. American College of Medical Genetics (ACMG). Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. February 2009; 11(2):127-133.
  37. Watson MS, Cutting GR, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. September/October 2004; 6(5):387-391.
  38. Sequencing-based Tests to Determine Trisomy 21 from Maternal Plasma DNA.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2013 January) OB/GYN/Reproduction 4.01.21.
History
September 2013  New 2013 BCBSMT medical policy.
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Prenatal and Preconception Genetic Tests