NONINVASIVE PRENATAL DIAGNOSIS OF FETAL ANEUPLOIDY USING CELL-FREE FETAL NUCLEIC ACIDS IN MATERNAL BLOOD

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1 CLINICAL POLICY NONINVASIVE PRENATAL DIAGNOSIS OF FETAL ANEUPLOIDY USING CELL-FREE FETAL NUCLEIC ACIDS IN MATERNAL BLOOD Policy Number: MATERNITY T2 Effective Date: May 1, 2013 Table of Contents CONDITIONS OF COVERAGE... COVERAGE RATIONALE BACKGROUND... CLINICAL EVIDENCE... U.S. FOOD AND DRUG ADMINISTRATION... APPLICABLE CODES... REFERENCES... POLICY HISTORY/REVISION INFORMATION... istory Revision Information The services described in Oxford policies are subject to the terms, conditions and limitations of the Member's contract or certificate. Unless otherwise stated, Oxford policies do not apply to Medicare Advantage enrollees. Oxford reserves the right, in its sole discretion, to modify policies as necessary without prior written notice unless otherwise required by Oxford's administrative procedures or applicable state law. The term Oxford includes Oxford Health Plans, LLC and all of its subsidiaries as appropriate for these policies. Certain policies may not be applicable to Self-Funded Members and certain insured products. Refer to the Member's plan of benefits or Certificate of Coverage to determine whether coverage is provided or if there are any exclusions or benefit limitations applicable to any of these policies. If there is a difference between any policy and the Member s plan of benefits or Certificate of Coverage, the plan of benefits or Certificate of Coverage will govern. CONDITIONS OF COVERAGE Page Related Policies: None Applicable Lines of Business/Products Benefit Type Referral Required (Does not apply to non-gatekeeper products) Authorization Required (Precertification always required for inpatient admission) Precertification with Medical Director Review Required Applicable Site(s) of Service (If site of service is not listed, Medical Director review is required) Special Considerations This policy applies to Oxford Commercial plan membership. General benefits package No Yes Yes 1 Laboratory 1 Precertification with review by a Medical Director or their designee is required. 1

2 COVERAGE RATIONALE DNA-based noninvasive prenatal tests of fetal aneuploidy (including, but not limited to, MaterniT21 PLUS, verifi or Harmony Prenatal Test ) are medically necessary as screening tools for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) or trisomy 13 (Patau syndrome) in ANY ONE of the following circumstances: Maternal age of 35 years or older at delivery Fetal ultrasound findings indicating an increased risk of aneuploidy History of a prior pregnancy with a trisomy Positive first- or second-trimester screening test results for aneuploidy Parental balanced Robertsonian translocation with an increased risk of fetal trisomy 13 or trisomy 21. DNA-based noninvasive prenatal tests of fetal aneuploidy (e.g., MaterniT21 PLUS, verifi or Harmony Prenatal Test ) are not medically necessary for pregnant women who do not meet the above criteria or women with multiple gestations. Further studies are needed to evaluate the use of these tests in low-risk populations or women with multiple gestations. Genetic Counseling Genetic counseling is strongly recommended prior to this test in order to inform persons being tested about the advantages and limitations of the test as applied to a unique person. Information Pertaining to Medical Necessity Review The above criteria apply to medical necessity review. BACKGROUND Humans have 23 pairs of chromosomes. Aneuploidy is an abnormal number of chromosomes. Trisomy is a type of aneuploidy in which there are three copies of a chromosome instead of two. Trisomy 21, also called Down syndrome, is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance and poor muscle tone (hypotonia) in infancy. The degree of intellectual disability varies, but it is usually mild to moderate. Individuals with Down syndrome may be born with a variety of birth defects including heart defects and digestive abnormalities. The risk of having a child with trisomy 21 increases with a mother s age (Genetics Home Reference, 2008). Down syndrome can also be caused by translocation, which occurs when a part of chromosome 21 breaks away and becomes attached to another chromosome. In a balanced translocation, pieces of chromosomes are rearranged but no genetic material is gained or lost in the cell. In these cases, the parent s health is not affected (Genetics Home Reference, December 2012). Trisomy 18, also called Edwards syndrome, is a chromosomal condition associated with slow growth before birth and a low birth weight. Affected individuals may have heart defects and abnormalities of other organs that develop before birth. Other features of trisomy 18 include a small, abnormally shaped head; a small jaw and mouth; and clenched fists with overlapping fingers. The risk of having a child with trisomy 18 increases with a mother s age (Genetics Home Reference, 2012). Trisomy 13, also called Patau syndrome, is a chromosomal condition associated with severe intellectual disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers and/or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate) and weak muscle tone (hypotonia). 2

3 The risk of having a child with trisomy 13 increases with a mother s age (Genetics Home Reference, 2009). Patau syndrome can also be caused by translocation. Current prenatal screening tests for trisomies 21, 18 and 13 combine maternal age with information from the measurement of maternal serum markers and ultrasound markers in the first and second trimesters of pregnancy. However, screening tests are used only to stratify risk and cannot be used to establish the diagnosis of a trisomy. Conventional prenatal diagnosis (i.e., chorionic villus sampling (CVS) or amniocentesis) can definitively diagnose fetal trisomies, although these invasive procedures are associated with a risk of miscarriage (Hayes, 2011). Tests proposed to detect fetal trisomies, without the need for CVS or amniocentesis, analyze cellfree DNA (cfdna) fragments in maternal blood. During pregnancy, there are cfdna fragments from both the mother and fetus in maternal circulation. The tests detect an increased amount of chromosomal material in maternal blood and can be offered as early as 10 weeks of pregnancy. cfdna analysis methods fall into two categories: massively parallel sequencing (MPSS) and directed DNA analysis. MPSS analyzes a random subset of cfdna fragments sampled from maternal blood. In directed analysis, specific cfdna fragments from maternal blood are used for selective sequencing. Because of the targeted sequencing, fewer cfdna fragments are needed for directed analysis (Ariosa website). All tests were validated in high-risk couples. It is unknown whether they are as accurate for low- to average risk couples. MaterniT21 The test was validated in high-risk couples with any one of the following risk factors: Advanced maternal age ( 35 years old at the time of delivery) Personal/family history of chromosomal abnormalities Fetal ultrasound abnormality suggestive of aneuploidy Positive serum screening test In February 2012, the company rebranded the MaterniT21 test under the name MaterniT21 PLUS, which includes the detection of trisomy 18 and trisomy 13, in addition to trisomy 21. The test is intended for use in patients at 10+ weeks gestation with singleton pregnancies who meet any one of the following criteria: Advanced maternal age Positive results of prenatal aneuploidy screening Presence of ultrasound abnormalities Previous affected pregnancy for fetal aneuploidy Verifi is not intended for women with multiple pregnancy (such as twins) or pregnancies conceived with an egg donor. Harmony Prenatal Test The Harmony Prenatal Test is intended for use in women with singleton pregnancies of at least 10 weeks gestation. The test is not intended for women with multiple pregnancy (such as twins) or pregnancies conceived with an egg donor. The Centers for Disease Control and Prevention (CDC) created the ACCE model process for evaluating genetic or genomic-based tests. The 4 main components of the ACCE process include analytic validity, clinical validity, clinical utility and ELSI. Analytic validity refers to how accurately and reliably the test measures the genotype of interest. Clinical validity refers to how consistently and accurately the test detects or predicts the intermediate or final outcomes of interest. Is what s measured associated with the outcome of interest? Clinical utility refers to how likely the test is to significantly improve patient outcomes. What is the clinical value? ELSI refers to the ethical, legal and social implications that may arise in the context of using the test (CDC, 2010). 3

4 CLINICAL EVIDENCE Analytic validity Verweij et al. (2012) conducted a systematic review on the diagnostic accuracy of noninvasive prenatal diagnosis (NIPD) of fetal trisomies using cell-free fetal DNA or RNA in maternal blood to detect fetal trisomy 21. With a total of 681 pregnancies included, overall sensitivity was 125/125 (100%) and specificity 552/556 (99.3%). NIPD of fetal trisomy 21, using fetal nucleic acids in maternal plasma, appears to have a high diagnostic accuracy. Large-scale prospective studies are awaited before implementation in clinical practice. Nicolaides et al. conducted a cohort study of 2049 pregnant women undergoing routine screening for aneuploidies at weeks' gestation. Plasma cell-free DNA analysis using chromosomeselective sequencing was used. Laboratory testing on a single plasma sample was carried out blindly and results were provided as risk score (%) for trisomies 21 and 18. Trisomy risk scores were given for 95.1% (1949 of 2049) of cases including all 8 with trisomy 21 and 2 of the 3 with trisomy 18. The trisomy risk score was >99% in the 8 cases of trisomy 21 and 2 of trisomy 18 and <1% in 99.9% (1937 of 1939) of euploid cases. The authors concluded that noninvasive prenatal testing (NIPT) using chromosome-selective sequencing in a routinely screened population identified trisomies 21 and 18 with a false-positive rate of 0.1%. However, the authors cautioned that because the sensitivity and specificity of NIPT is not 100%, the test should not be considered a diagnostic replacement for invasive testing in high-risk pregnancies. MaterniT21 Canick et al. (2012) conducted a study on prenatal testing for Down syndrome (trisomy 21), trisomy 18 and trisomy 13 by massively parallel shotgun sequencing (MPSS) of circulating cell free DNA in pregnant women with multiple gestations. Among a cohort of 4664 high-risk pregnancies, maternal plasma samples were tested from 25 twin pregnancies (17 euploid, five discordant and two concordant for Down syndrome; one discordant for trisomy 13) and two euploid triplet pregnancies. Seven twin pregnancies with Down syndrome, one with trisomy 13, and all 17 twin euploid pregnancies were correctly classified [detection rate 100%, false positive rate 0%], as were the two triplet euploid pregnancies. Although study size is limited, the authors concluded that this data provides evidence that MPSS testing can be reliably used as a secondary screening test for Down syndrome in women with high-risk twin gestations. Further studies, with larger patient populations, are needed to confirm these results. Studies indicate that the sensitivity of MaterniT21 for detecting fetal trisomy 21 ranges from 97% to 100%, when no more than 4 samples were analyzed simultaneously (i.e., multiplexed). The specificity of the analysis ranges from 97.9% to 99.8%, with a false-positive rate of 0.2% to 2.1%. However, 5.6% to 6.5% of study samples were excluded from analysis after failing preanalytic quality control measures, such as inadequate volume or inappropriate sample processing, and sequence failure rates up to 4.4% have been reported. The data also showed that the performance of the assay depends on the guanine-cytosine (GC) content of the chromosome being analyzed (referred to as GC bias), and that the proportion of fetal DNA in maternal plasma correlates with both gestational age and maternal weight, with higher levels later in gestation and in women with lower body weights. While published studies of analytical validity provide promising results, larger publicly funded trials involving standardized study protocols, uniform methods of analysis and specific, well-defined patient populations need to be performed (Hayes, 2011). In the largest and most comprehensive study to date, Palomaki et al. (2011) evaluated the analytic validity of a noninvasive prenatal screening test for Down syndrome that measures circulating cell-free DNA in maternal plasma. Test results were compared to those obtained after chorionic villus sampling or amniocentesis. A total of 4664 pregnant women, each considered at high risk for having a child with trisomy 21 (based on maternal age, screening test results and/or ultrasound results), were recruited from 27 prenatal diagnostic centers and included in this blinded, nested case-control study. Of the 4664 cases, 279 (6%) were excluded from the analysis for various reasons. Of the remaining cases, 218 (5%) fetuses were diagnosed with trisomy 21 based on the results of invasive testing. The first 212 cases were selected for analysis. Fetal 4

5 karyotyping was compared with an internally validated, laboratory-developed test based on nextgeneration sequencing. Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471) and the testing failed in 13 pregnancies (0.8%). The authors concluded that, when applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Using the same cohort of patients, Palomaki et al. (2012) reported additional data indicating that maternal plasma cell-free DNA sequencing also has the capability to detect other aneuploidies, such as trisomy 18 and trisomy 13. Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were included in the analysis. Among the 99.1% of samples interpreted, observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) with false-positive rates of 0.28% and 0.97%, respectively. Chiu et al. (2011) validated the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling. The diagnostic accuracy was validated against full karyotyping, using prospectively collected or archived maternal plasma samples. Results were available from 753 pregnancies with the 8-plex sequencing protocol and from 314 pregnancies with the 2-plex protocol. The performance of the 2-plex protocol was superior to that of the 8-plex protocol. With the 2-plex protocol, trisomy 21 fetuses were detected at 100% sensitivity and 97.9% specificity, which resulted in a positive predictive value of 96.6% and negative predictive value of 100%. The 8-plex protocol detected 79.1% of the trisomy 21 fetuses and 98.9% specificity, giving a positive predictive value of 91.9% and negative predictive value of 96.9%. The authors concluded that multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. Ehrich et al. (2011) evaluated a multiplexed massively parallel shotgun sequencing assay for noninvasive trisomy 21 detection using circulating cell-free fetal DNA. A total of 480 plasma samples from high-risk pregnant women were analyzed. Thirteen samples were removed due to insufficient quantity or quality. Eighteen samples failed prespecified assay quality control parameters. In all, 449 samples remained: 39 trisomy 21 samples were correctly classified; 1 sample was misclassified as trisomy 21. The overall classification showed 100% sensitivity and 99.7% specificity. The authors reported that extending the scope of previous reports, these results warrant clinical validation in a larger multicenter study. Fan et al. (2008) were the first to evaluate the analytic validity of a sequencing protocol for the analysis of cell-free DNA in maternal plasma and the noninvasive prenatal diagnosis of fetal aneuploidy. Subjects included 18 women with an increased risk of having a child with aneuploidy. Fetal karyotyping indicated that 9 fetuses had trisomy 21, 2 had trisomy 18, 1 had trisomy 13 and 6 had no evidence of aneuploidy. The sequencing protocol accurately identified all 18 cases. Trisomy was detected at gestational ages as early as the 14th week. verifi The MELISSA (MatErnal Blood IS Source to Accurately Diagnose Fetal Aneuploidy) trial was conducted as a prospective, multicenter observational study to determine the diagnostic accuracy of massively parallel sequencing (verifi ) to detect fetal aneuploidy from maternal plasma. Blood samples were collected from 2,882 women undergoing invasive prenatal diagnostic procedures. Within an analysis cohort, the following were classified correctly: 89 of 89 trisomy 21 cases (sensitivity 100%, 95% CI), 35 of 36 trisomy 18 cases (sensitivity 97.2%, 95% CI) and 11 of 14 trisomy 13 cases (sensitivity 78.6%, 95% CI). The authors reported high sensitivity and specificity for the detection of trisomies 21, 18, 13 in women with singleton pregnancies at an increased risk for aneuploidy. Further studies are needed to build confidence in the diagnostic performance of the test in low-risk populations and in multiple gestations. ClinicalTrials.gov NCT (Bianchi et al., 2012). Sehnert et al. (2011) evaluated an optimized algorithm for use with massively parallel DNA sequencing of cell-free fetal DNA to detect fetal chromosomal abnormalities. Existing algorithms 5

6 focus on the detection of fetal trisomy 21 (T21); however, these same algorithms have difficulty detecting trisomy 18 (T18). Blood samples were collected from 1014 patients prior to undergoing an invasive prenatal procedure. The DNA extracted from 119 samples underwent massively parallel DNA sequencing. Fifty-three sequenced samples came from women with an abnormal fetal karyotype. To minimize the intra- and interrun sequencing variation, investigators developed an optimized algorithm by using normalized chromosome values (NCVs) from the sequencing data on a training set of 71 samples with 26 abnormal karyotypes. The classification process was then evaluated on an independent test set of 48 samples with 27 abnormal karyotypes. Sequencing of the independent test set led to 100% correct classification of T21 (13 of 13) and T18 (8 of 8) samples. Other chromosomal abnormalities were also identified. The authors concluded that massively parallel sequencing is capable of detecting multiple fetal chromosomal abnormalities from maternal plasma when an optimized algorithm is used. Harmony Prenatal Test Norton et al. conducted a multicenter cohort study evaluating the performance of a noninvasive prenatal test for fetal trisomy 21 (T21) and trisomy 18 (T18) using cell-free DNA from maternal plasma. Chromosome-selective sequencing was performed with reporting of an aneuploidy risk (high risk or low risk) for each subject. Of the 81 T21 cases, all were classified as high risk for T21 and there was 1 false-positive result among the 2888 normal cases, for a sensitivity of 100% and a false-positive rate of 0.03%. Of the 38 T18 cases, 37 were classified as high risk and there were 2 false-positive results among the 2888 normal cases, for a sensitivity of 97.4% and a falsepositive rate of 0.07%. The authors concluded that chromosome-selective sequencing of cell-free DNA and application of an individualized risk algorithm is effective in the detection of fetal T21 and T18. Sparks et al. (2012) evaluated a novel biochemical assay and algorithm for the prenatal evaluation of risk for fetal trisomy 21 (T21) and trisomy 18 (T18) using cell-free DNA obtained from maternal blood. In a blinded analysis of 167 pregnant women, digital analysis of selected regions (DANSR), in combination with a novel algorithm, fetal-fraction optimized risk of trisomy evaluation (FORTE), correctly identified all 36 cases of T21 and 8 cases of T18. The investigators assayed cell-free DNA from a training set and a blinded validation set of pregnant women, comprising 250 disomy, 72 T21 and 16 T18 pregnancies. 163/171 subjects in the training set passed quality control criteria. FORTE produced an individualized trisomy risk score for each subject, and correctly discriminated all T21 and T18 cases from disomic cases. All 167 subjects in the blinded validation set passed quality control and FORTE performance matched that observed in the training set correctly discriminating 36/36 T21 cases and 8/8 T18 cases from 123/123 disomic cases. The authors concluded that while DANSR and FORTE enable accurate noninvasive fetal aneuploidy detection in a high-risk population, larger studies that include lowand average-risk pregnancies are needed. In a nested case-control study, Ashoor et al. (2012) assessed the prenatal detection rate of trisomy 21 and 18 by chromosome-selective sequencing of maternal plasma cell-free DNA. Cellfree DNA was examined in stored plasma that was obtained at weeks before chorionic villous sampling from 300 euploid pregnancies, 50 pregnancies with trisomy 21 and 50 pregnancies with trisomy 18. The authors reported that the sensitivity for detecting trisomy 21 was 100% (50/50 cases); the sensitivity for trisomy 18 was 98% (49/50 cases) and the specificity was 100% (297/297 cases). Clinical validity No studies designed specifically to evaluate the clinical validity of these tests were identified. However, some studies of analytic validity compare the results of the analyses to the current reference standard for the prenatal diagnosis of trisomies (i.e., CVS or amniocentesis). Therefore, these findings may also support the clinical validity of these tests (Hayes, 2011). Clinical utility No studies evaluating the impact of these tests on patient management or outcomes were identified. Prospective data is needed in which test results are acted upon clinically, showing that results lead to a change in patient management and/or outcomes (Simpson, 2012). For example, 6

7 data must demonstrate that physicians have sufficient confidence in both positive and negative test results to refrain from performing more invasive testing, e.g., amniocentesis, for the purpose of confirming the previously obtained test results. Professional Societies American College of Medical Genetics (ACMG) A clinical practice guideline from ACMG does not address the use of DNA-based prenatal tests for fetal aneuploidy (Driscoll and Gross, 2009). American College of Obstetricians and Gynecologists (ACOG) ACOG recommends that women, regardless of maternal age, be offered prenatal assessment for aneuploidy. Cell free fetal DNA is one option that can be used as a primary screening test in women at increased risk of aneuploidy. This includes women aged 35 years or older, fetuses with ultrasound findings that indicate an increased risk of aneuploidy, women with a history of a child affected with a trisomy or a parent carrying a balanced Robertsonian translocation with increased risk of trisomy 13 or trisomy 21. It can also be used as a follow-up test for women with a positive first- or second-trimester screening test result. ACOG further states that cell free fetal DNA testing should be an informed patient choice after pretest counseling and should not be part of routine prenatal laboratory assessment. 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. 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 should be offered invasive prenatal diagnosis for confirmation of test results (ACOG, 2012). National Society of Genetic Counselors (NSGC) The NSGC currently supports noninvasive prenatal testing/noninvasive prenatal diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities. NSGC urges that NIPT/NIPD only be offered in the context of informed consent, education and counseling by a qualified provider, such as a certified genetic counselor. Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing. Adopted February 18, 2012 (NSGC website). U.S. FOOD AND DRUG ADMINISTRATION (FDA) Laboratories that perform DNA-based prenatal tests for trisomy 21, 18 and 13 are regulated by the FDA under the Clinical Laboratory Improvement Amendments. See the following web site for more information: m htm. Accessed December 31, APPLICABLE CODES The codes listed in this policy are for reference purposes only. Listing of a service or device code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the Member s plan of benefits or Certificate of Coverage. This list of codes may not be all inclusive. CPT Code Description 0005M 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 Unlisted molecular pathology procedure (effective 1/1/2013) Unlisted multianalyte assay with algorithmic analysis (effective 1/1/2013) 7

8 CPT Code Description Unlisted chemistry procedure CPT is a registered trademark of the American Medical Association. ICD-9 Diagnosis Code Description Chromosomal abnormality in fetus, affecting management of mother, unspecified as to episode of care in pregnancy Chromosomal abnormality in fetus, affecting management of mother, with delivery Chromosomal abnormality in fetus, affecting management of mother, antepartum Elderly primigravida, unspecified as to episode of care Elderly primigravida, antepartum Elderly multigravida, unspecified as to episode of care or not applicable Elderly multigravida, with antepartum condition or complication Other conditions due to autosomal anomalies V23.81 Supervision of high-risk pregnancy of elderly primigravida V23.82 Supervision of high-risk pregnancy of elderly multigravida ICD-10 Codes (Preview Draft) In preparation for the transition from ICD-9 to ICD-10 medical coding on October 1, 2014 *, a sample listing of the ICD-10 CM and/or ICD-10 PCS codes associated with this policy has been provided below for your reference. This list of codes may not be all inclusive and will be updated to reflect any applicable revisions to the ICD-10 code set and/or clinical guidelines outlined in this policy. *The effective date for ICD-10 code set implementation is subject to change. ICD-10 Diagnosis Code Description (Effective 10/1/2014) Q92.0 Whole chromosome trisomy, nonmosaicism (meiotic nondisjunction) Q92.1 Whole chromosome trisomy, mosaicism (mitotic nondisjunction) Q92.2 Partial trisomy Q92.5 Duplications with other complex rearrangements Q92.7 Triploidy and polyploidy Q92.8 Other specified trisomies and partial trisomies of autosomes Q92.9 Trisomy and partial trisomy of autosomes, unspecified Q93.0 Whole chromosome monosomy, nonmosaicism (meiotic nondisjunction) Q93.1 Whole chromosome monosomy, mosaicism (mitotic nondisjunction) Q95.2 Balanced autosomal rearrangement in abnormal individual Q99.8 Other specified chromosome abnormalities O Supervision of elderly primigravida, unspecified trimester O Supervision of elderly primigravida, first trimester O Supervision of elderly primigravida, second trimester O Supervision of elderly primigravida, unspecified trimester O Supervision of elderly multigravida, unspecified trimester O Supervision of elderly multigravida, first trimester O Supervision of elderly multigravida, second trimester O Supervision of elderly multigravida, unspecified trimester O Supervision of elderly primigravida, first trimester O Supervision of elderly primigravida, second trimester O Supervision of elderly primigravida, unspecified trimester 8

9 REFERENCES The foregoing Oxford policy has been adapted from an existing UnitedHealthcare national policy that was researched, developed and approved by UnitedHealthcare Medical Technology Assessment Committee. [2013T0560B] ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77. Screening for fetal chromosomal abnormalities. Obstet Gynecol Jan;109(1): American College of Obstetricians and Gynecologists (ACOG). Committee Opinion No Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol Dec;120(6): Ariosa Diagnostics website. Harmony Prenatal Test. Available at: Accessed December 31, 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;206(4):322.e1-5. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol May;119(5): 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 Aug;32(8): Centers for Disease Control and Prevention (CDC). Genomic Testing. Available at: Accessed December 31, Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ Jan 11;342:c7401. Driscoll DA, Gross SJ; Professional Practice Guidelines Committee. Screening for fetal aneuploidy and neural tube defects. Genet Med Nov;11(11): Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med Jun 11;360(24): ECRI Institute. Hotline Service. Cell-free fetal DNA tests for prenatal screening of chromosomal aneuploidies. July 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;204(3):205.e1-11. Fan HC, Blumenfeld YJ, Chitkara U, et al. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci U S A Oct 21;105(42): Genetics Home Reference website. Down syndrome. June Available at: Accessed December 31, Genetics Home Reference website. Trisomy 18. March Available at: Accessed December 31, Genetics Home Reference website. Trisomy 13. January Available at: Accessed December 31,

10 Genetics Home Reference website. Can changes in the structure of chromosomes affect health and development? December Available at: Accessed December 31, Hayes, Inc. GTE Report. MaterniT21 noninvasive prenatal test for trisomy 21 (Down syndrome). Hayes, Inc; Lansdale, PA. December National Society of Genetic Counselors (NSGC). Position statement. Noninvasive prenatal testing/noninvasive prenatal diagnosis. February Available at: Accessed December 31, 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 Nov;207(5):374.e1-6. 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;207(2):137.e1-8. 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;13(11): 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;14(3): 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;57(7): Sequenom CMM website. MaterniT21 PLUS. Available at: Accessed December 31, Simpson JL. Is cell-free fetal DNA from maternal blood finally ready for prime time? Obstet Gynecol May;119(5): Sparks AB, Struble CA, Wang ET, Song K, Oliphant A. 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;206(4):319.e1-9. Verinata Health website. verifi. Available at: Accessed December 31, Verweij EJ, van den Oever JM, de Boer MA, et al. Diagnostic accuracy of noninvasive detection of fetal trisomy 21 in maternal blood: a systematic review. Fetal Diagn Ther. 2012;31(2):81-6. POLICY HISTORY/REVISION INFORMATION Date 05/01/2013 Action/Description Updated description of services to reflect most current clinical evidence, FDA information, and references Reformatted policy content Revised coverage rationale to indicate: o DNA-based noninvasive prenatal tests of fetal aneuploidy (including, but not limited to, MaterniT21 PLUS, verifi or 10

11 Date o o Action/Description Harmony Prenatal Test ) are proven as screening tools for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) or trisomy 13 (Patau syndrome) in ANY ONE of the following circumstances: Maternal age of 35 years or older at delivery Fetal ultrasound findings indicating an increased risk of aneuploidy History of a prior pregnancy with a trisomy Positive first- or second-trimester screening test results for aneuploidy Parental balanced Robertsonian translocation with an increased risk of fetal trisomy 13 or trisomy 21 DNA-based noninvasive prenatal tests of fetal aneuploidy (e.g., MaterniT21 PLUS, verifi or Harmony Prenatal Test ) are unproven for pregnant women who do not meet the above criteria or women with multiple gestations Genetic counseling is strongly recommended prior to this test in order to inform persons being tested about the advantages and limitations of the test as applied to a unique person o The criteria above applies to medical necessity review Updated list of applicable CPT codes; added 0005M, and (new codes effective 01/01/13) Added list of applicable ICD-9 diagnosis codes: , , , 659.5, , , , 758.5, V23.81, and V23.82 Added list of applicable ICD-10 diagnosis codes (preview draft effective 10/01/14) Archived previous policy version MATERNITY