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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Obstetrics
Policy Number:017
Effective Date:
Original Policy Date:07/24/2012
Last Review Date:08/11/2015
Date Published to Web: 02/25/2015
Noninvasive Prenatal Screening for Fetal Aneuploidies Using Cell-Free Fetal DNA



The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.


National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, most of which are aneuploidies (an abnormal number of chromosomes). The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome trisomies 21 (T21), 18 (T18), and 13 (T13) are the most common forms of fetal aneuploidy that survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Noninvasive prenatal testing analyzing cell-free fetal DNA in maternal serum is a potential complement or alternative to conventional serum screening.

Patients/individuals with:
ˇ Desire to test for fetal aneuploidies during pregnancy
Interventions of interest are:
ˇ Noninvasive prenatal screening for fetal aneuploidies using cell-free fetal DNA
Comparators of interest are:
ˇ Conventional serum screening, with or without ultrasound markers
Relevant outcomes include:
ˇ Resource utilization
ˇ Treatment-related morbidity
ˇ Test accuracy

Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. Most fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. The most important risk factor for trisomy syndromes is maternal age, with an approximate risk of 1 in 1500 in young women that increases to nearly 1 in 10 by age 48.

Trisomy 21 (T21, Down syndrome) is the most common cause of human birth defects and provides the impetus for current maternal serum screening programs. Other trisomy syndromes include T18 (Edwards syndrome), and T13 (Patau syndrome), which are the next most common forms of fetal aneuploidy, although the percentage of cases surviving to birth is low and survival beyond birth is limited. The prevalence of these other aneuploidies is much lower than the prevalence of T21, and identifying them is not currently the main intent of prenatal screening programs. Also, the clinical implications of identifying trisomy 18 and 13 are unclear, as survival beyond birth is limited for both conditions.

Sex chromosome aneuploidies (eg, 45,X [Turner syndrome]; 47,XXY, 47,XYY) occur in approximately 1 in 400 live births. These aneuploidies are typically diagnosed postnatally, sometimes not until adulthood, such as during an evaluation of diminished fertility. Alternatively, sex chromosome aneuploidies may be diagnosed incidentally during invasive karyotype testing of pregnant women at high risk for Down syndrome. The net clinical value of prenatal diagnosis of sex chromosome aneuploidies is unclear. Potential benefits of early identification such as 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.

Current national guidelines recommend that all pregnant women be offered screening for fetal aneuploidy (referring specifically to T21, T18, T13) before 20 weeks of gestation, regardless of age.1 Combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy are used, but there is not a standardized approach. The detection rate for various combinations of noninvasive testing ranges from 60% to 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 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 potentially improve outcomes.

Commercial, noninvasive, sequencing-based testing of maternal serum for fetal trisomy syndromes is now available and has the potential to substantially alter the current approach to screening. The test technology involves detection of fetal cell-free DNA fragments present in the plasma of pregnant women. As early as 8 to 10 weeks of gestation, these fetal DNA fragments comprise 6% to 10% or more of the total cell-free DNA in a maternal plasma sample. The tests are unable to provide a result if fetal fraction is too low, that is, below about 4%. Fetal fraction can be affected by maternal and fetal characteristics. For example, fetal fraction was found to be lower at higher maternal weights and higher with increasing fetal crown-rump length.2

Sequencing-based tests use 1 of 2 general approaches to analyzing cell-free DNA. The first category of tests uses quantitative or counting methods. The most widely used technique to date uses massively parallel sequencing (MPS; also known as next-generation or “next gen” sequencing). DNA fragments are amplified by polymerase chain reaction; during the sequencing process, the amplified fragments are spatially segregated and sequenced simultaneously in a massively parallel fashion. Sequenced fragments can be mapped to the reference human genome to obtain numbers of fragment counts per chromosome. The sequencing-derived percent of fragments from the chromosome of interest reflects the chromosomal representation of the maternal and fetal DNA fragments in the original maternal plasma sample. Another technique is direct DNA analysis, which analyzes specific cell-free DNA fragments across samples and requires approximately a tenth the number of cell-free DNA fragments as MPS. The digital analysis of selected regions (DANSR™) is an assay that uses direct DNA analysis.

The second general approach is single nucleotide polymorphism (SNP)-based methods. These use targeted amplification and analysis of approximately 20,000 SNPs on selected chromosomes (eg, 21, 18, 13) in a single reaction. A statistical algorithm is used to determine the number of each type of chromosome.

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. In its most recent guidance, issued online in June 2015, ACOG recommends diagnostic testing to confirm positive cell-free DNA tests.

Regulatory Status
None of the commercially available sequencing assays for detection of T21, T18, and T13 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 [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. Commercially available tests include but are not limited to the following:
    ˇ Sequenom MaterniT21™ PLUS test. Tests for trisomy 21, 18 and 13 and also reports fetal sex aneuploidies, trisomies 16 and 22, and selected microdeletions as additional findings. The test uses MPS and reports results as positive or negative.
    ˇ 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.)
    ˇ Natera Panorama™ prenatal test. Tests for detecting trisomy 21, 18 and 13, as well as for detecting select sex chromosome abnormalities. Uses SNP technology; results reported as risk score.
    ˇ Illumina (formerly Verinata Health, which it acquired) VerifiŽ 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.
    ˇ 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.
    ˇ Quest Diagnostics QNatal™ Advanced Tests for trisomies 21, 18, and 13.

Related Policies
  • First Trimester Screening for Chromosomal Abnormalities using Fetal Ultrasound Assessment of Nuchal Translucency Combined with Maternal Serum Assessment (Policy #008 in the Obstetrics Section)

1. Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered medically necessary in women with singleton pregnancies undergoing screening for trisomy 21. (Karyotyping would be necessary to exclude the possibility of a false positive nucleic acid sequencing–based test. Before testing, women should be counseled about the risk of a false positive test (see Policy Guidelines section).

2. Concurrent nucleic acid sequencing-based testing of maternal plasma for trisomy 13 and/or 18 is considered medically necessary in women who are eligible for and are undergoing nucleic acid sequencing-based testing of maternal plasma for trisomy 21.

3. Nucleic acid sequencing-based testing of maternal plasma for trisomy 21 is considered investigational in women with twin or multiple pregnancies.

4. Nucleic acid sequencing-based testing of maternal plasma for trisomy 13 and/or 18, other than in the situations specified above, is considered investigational.

5. Nucleic acid sequencing-based testing of maternal plasma for fetal sex chromosome aneuploidies is considered investigational.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

In a 2015 committee opinion, the American College of Obstetricians and Gynecologists (ACOG) recommends that all patients receive information on the risks and benefits of various methods of prenatal screening and diagnostic testing, including the option of no testing.

Studies published to date report rare but occasional false positives. In these studies, the actual false-positive test results were not always borderline; some were clearly above the assay cutoff value, and no processing or biological explanations for the false-positive results were reported. False-positive findings have been found to be associated with factors including placental mosaicism, vanishing twins, and maternal malignancies. In its 2015 committee opinion, ACOG recommended diagnostic testing to confirm positive cell-free DNA tests, and that management decisions not be based solely on the results of cell-free DNA testing. ACOG further recommends that patients with indeterminate or uninterpretable (ie, “no call”) cell-free DNA test results be referred for genetic counseling and offered ultrasound evaluation and diagnostic testing because “no call” findings have been associated with an increased risk of aneuploidy.

As noted in the 2015 ACOG committee opinion, cell-free DNA screening does not assess risk of anomalies such as neural tube defects. Patients should continue to be offered ultrasound or maternal serum alpha-fetoprotein screening, regardless of the type of serum screening selected.

In some cases, tissue samples from chorionic villous sampling (CVS) or amniocentesis may be insufficient for karyotyping; confirmation by specific fluorescent in situ hybridization (FISH) assay is acceptable for these samples.

[RATIONALE: Literature on average- risk women was reviewed through June 29, 2015. Moreover, the policy is informed by 2 TEC Assessments. A 2013 TEC Assessment focused on detection of trisomy 213 and a 2014 TEC Assessment addressed detection of fetal aneuploidies other than T21 (specifically trisomies 13 and 18, and fetal sex chromosome aneuploidies).4 The policy limits its 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 (ie, 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 is described next.

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 [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 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 next generation sequencing, NGS, that would assure safety and effectiveness of devices marketed for clinical diagnostics.”5 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 T21 has developed a specific procedure for its private, CLIA-licensed laboratory where all testing takes place.

Section Summary
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 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 Fetal Aneuploidies Compared With the Criterion Standard of Karyotype Analysis?

High-Risk Pregnancies
A 2014 meta-analysis by Gil et al searched for studies published through December 2013 on the diagnostic performance of sequencing-based tests in identifying trisomies T21, T18, and T13.6 A total of 18 studies on T21 were identified; the studies included a combined total of 809 T21 and 12,272 non-T21 pregnancies. Sixteen of the 18 studies were conducted in high-risk singleton pregnancies, so these data are considered in the section on high-risk pregnancies. The pooled weighted detection rate for T21 was 99.0% (95% confidence interval [CI], 98.2 to 99.6) and the pooled weighted false-positive rate was 0.08% (95% CI, 0.03 to 0.14). Fifteen studies reported on T18; a total of 301 trisomy 18 and 11,646 non-T18 singleton pregnancies were included. The pooled weighted detection rate for T18 was 96.8% (95% CI, 94.5 to 98.4) and the pooled false-positive rate was 0.15% (95% CI, 0.08 to 0.25). Finally, 11 studies reported on the performance of the tests in identifying T13. The studies included a total of 85 trisomy 13 and 8339 non-T13 singleton pregnancies. The pooled weighted detection rate and false-positive rate were 92.1% (95% CI, 85.9% to 96.7%) and 0.2% (95% CI, 0.04 to 0.46). This systematic review was not limited to tests available in the United States.

The 2014 TEC Assessment included a meta-analysis of sequencing-based studies published through April 15, 2014 that reported on T18, T13 and/or sex chromosome anomalies.4 Analyses were conducted on the overall population, and, for T18 and T13, separately for the studies on high-risk and low-risk pregnancies. Findings in the high-risk pregnancy population are presented in Table 1.

Table 1: Findings from 2014 TEC Assessment Meta-Analysis Overall and in High-Risk Pregnancies (Trisomy 13 and Trisomy 18)
No. of Studies
Pooled Sensitivity
Pooled Specificity
84% (95% CI, 71% to 92%)
(115 cases, 8 false-negatives)
99% (95% CI, 99% to 100%)
(22 false-positives)
High risk
84% (95% CI, 71% to 92%)
(110 cases, 8 false-negatives)
99% (95% CI, 99% to 99%)
(21 false-positives)
15 sensitivity
22 specificity
95% (95% CI, 90% to 97%)
(392 cases, 21 false-positives)
100% (95% CI, 99% to 100%)
(22 false-positives)
High risk
95% (95% CI, 90% to 97%)
(344 cases, 10 false-negatives)
100% (95% CI, 99% to 100%)
(17 false-positives)
CI: confidence interval.

For sex chromosome anomalies, the largest number of studies (14 studies, total of 152 cases) addressed detection of monosomy X. Pooled sensitivity for detecting monosomy X was 83% (95% CI, 74% to 90%) and pooled specificity was 100% (95% CI, 100% to 100%). In addition, 11 studies with a total of 51 cases were identified on the performance of sequencing-based tests in identifying other sex chromosome anomalies. Pooled sensitivity was 89% (95% CI, 50% to 98%) and pooled specificity was 100% (100% to 100%). The meta-analysis of studies on sex chromosome aneuploidies did not differentiate between high- and low-risk populations.

Key studies evaluating sequencing-based tests for detecting T21 (and, when available T18, T13) in high-risk singleton pregnancies are summarized in Appendix Table 1.7-16 Sensitivity and specificity of the tests, as shown in Table 1, were uniformly high. Sensitivity ranged from 99.1% to 100%, and specificity from 99.7% to 100%. Studies are available from all 4 companies currently marketing tests in the United States. Most were prospective, and most were industry-funded. Studies generally included women at a wide range of gestational ages (eg, 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 (ie, nested case-control analysis within a cohort). The studies evaluated the results of maternal fetal DNA testing in comparison with the criterion standards of karyotyping or, in individual cases when a sample did not allow karyotyping, fluorescence in situ hybridization for specific trisomies.

Section Summary
Data from the available published studies consistently reported a very high sensitivity and specificity of maternal plasma DNA sequencing–based tests for detecting T21 in high-risk women with singleton pregnancies. There are fewer data on the diagnostic performance of sequencing-based tests for detecting T13, T18, and sex chromosome aneuploidies. The available data suggest that diagnostic performance for detecting these other fetal aneuploidies is not as high as it is for detection of T21.

Average-Risk Pregnancies
Fewer studies have been published on maternal plasma DNA sequencing–based tests for detection of T21 in average-risk women. Data on sensitivity and specificity from the available studies are summarized in Appendix Table 2.

The Illumina test (Verifi) was evaluated in a general population sample in a 2014 study by Bianchi et al.17 The study enrolled 2052 women with singleton pregnancies at least 8 weeks of gestation. Another eligibility criterion was a completed or planned standard prenatal serum screening during the first and/or second trimester. The blood sample for sequencing-based testing was not required to be taken at the same time as standard screening, so women beyond the second trimester remained eligible for study participation. A total of 40% of the sample were in their first trimester, 32% in the second trimester and 28% in the third trimester. The reference standard was newborn physical examination in 97% of cases and karyotype analysis in the remaining 3% of cases. Screening was incomplete for 39 patients, and 10 others did not have an adequate blood sample. A total of 1914 patients remained, although numbers varied somewhat in the different analyses.

The primary study outcome was the false-positive rate of sequencing-based testing compared with standard prenatal screening; this analysis excluded all cases of true aneuploidy. (Numbers varied somewhat in the different analyses). For the detection of T21, there were 6 of 1909 (0.3%) false positives with sequencing-based testing and 69 of 1909 (3.6%) false positive with standard testing. The difference between groups was statistically significant, favoring sequencing-based testing. The relative sensitivity of the tests was a secondary outcome. There were 5 cases of T21; both techniques correctly identified all of these cases. A limitation of the study was the small number of T21 cases included in the analysis. Moreover, most patients were in the second or third trimester of pregnancy when blood was drawn and had a higher fetal fraction of DNA than samples drawn earlier in pregnancy at the time that the test would most likely be used in practice.

Several studies have evaluated the Ariosa test (Harmony) in average-risk singleton pregnancies. This test provides risk scores rather than a positive versus negative result. In 2012, Nicolaides et al evaluated archived samples from 2049 women attending their routine first pregnancy visit at 11 to 14 weeks of gestation.18 Karyotyping results were available for only a small percentage of women in the study; for the rest of the enrollees, ploidy was imputed by phenotype at birth obtained from medical records. This study was judged to have a high risk of bias due to a high number of exclusions from analysis. Twenty-eight pregnancies ending in stillbirth or miscarriage were excluded for lack of karyotype; while unavoidable, these exclusions likely affect the case detection rate. Results were available for 1949 of 2049 cases (95%). In the remaining 5%, either the fetal fraction was too low or the assay failed. Overall, using the risk cutoff for the Harmony test, the trisomy detection rate was 100% (ie, 10/10 cases identified), and there was a false-positive rate of 0.1%. The risk score was over 99% in all of the 8 cases of trisomy and both cases of T18. In the 1939 known or presumed euploid cases, risk scores for T21 and T18 were less than 0.01% in 1939 (99.9%).

Next, the investigators conducted a 2-part prospective study that evaluated a testing strategy consisting of analysis of serum markers (ie, pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin) and cell-free DNA at 10 weeks and ultrasound markers (ie, nuchal translucency and presence or absence of fetal nasal bone) at 12 weeks. In the first part of the study, Gill et al prospectively studied 1005 pregnant women.19 Parents were counseled primarily on the finding of the Harmony test if it indicated either a high or low risk of trisomy. If no results were available on the Harmony test, parents were counseled based on combined first-trimester serum marker and ultrasound findings. Risk scores from cell-free DNA testing were available for 984 cases (98%); 27 of these required a second round of sampling. Risk scores were greater than 99% for T21 in 11 cases and for T18 in 5 cases. In 1 case, the risk score for T13 was 34%. Sixteen of the 17 women with a high risk score for aneuploidy underwent chorionic villous sampling (CVS) and the suspected abnormality was confirmed in 15 of the 16 cases. There was 1 case with a high risk score for T21 and a negative CVS; at the time the article was written, the woman was still pregnant so the presence or absence of T21 could not be confirmed.

In part 2 of the study, published in 2014 by Quezada et al, results of the combined test were used to estimate risk of each trisomy for all patients.20 A total of 2905 women were included in this second analysis (it is not clear whether there is overlap between patients included here and in the 2013 study by Gil et al). According to the reference standard (ie, fetal karyotyping or clinical examination of neonates), there were 34 cases of T21, 10 of T18, and 5 of T13. Cell-free DNA identified 32 of 34 (94%) cases of T21, and all cases of T18 and T13 as high risk. Combined testing with maternal serum markers and fetal ultrasound markers identified all cases of T21, T18 and T13. Of 2787 nontrisomic cases, cell-free DNA correctly identified 2730 (97.95%) as low risk and combined testing identified 2663 (95.55%) as low risk. With cell-free DNA, 8 nontrisomic cases were considered high risk, and there was no result for 49. Combined testing incorrectly identified 124 nontrisomic cases as high risk.

In 2015, Norton et al published a large study evaluating cell-free fetal DNA testing in a general population sample.20 The study included 15,841 adult women undergoing routine first-trimester aneuploidy screening. Patients needed to have a singleton pregnancy between 10.0 and 14.3 weeks of gestation at the time of the blood draw. Patients underwent both cell-free DNA (cfDNA) test (Harmony test, Ariosa) and standard screening (maternal serum markers and nuchal translucency), The reference standard was pregnancy and newborn outcomes (including miscarriages, terminations, delivery).

The study’s primary outcome was the area under the receiver operating characteristic curve (AUC) for T21 screening with cell-free DNA versus standard screening for women with complete results on the 2 tests. A positive result on standard screening was a risk of at least 1 in 270 for T21. A positive result on cell-free DNA screening was a risk of 1 in 100 or higher according to proprietary algorithms that took into account cell-free DNA counts, fetal fraction of cell-free DNA, and trisomy risk based on maternal and gestational age. The authors also conducted a preplanned subanalysis in “low-risk” patients, defined in 2 ways: women younger than 35 years old, and women who had a risk of T21 of less than 1 in 270 on standard screening.

A total of 15,841 of 18,955 (83.6%) of enrolled women were included in the primary analysis cohort. Chromosomal anomalies were identified in 68 of 15,841 pregnancies. There were 38 cases of T21, 10 cases of T18, 6 cases of T13, and the remaining cases were less common aneuploidies. The AUC for T21 was 0.999 for cell-free DNA testing and 0.958 for standard screening (p=0.001).

Of the 38 participants with T21, cell-free DNA identified all cases (sensitivity, 100%; 95% CI, 90.7 to 100) and standard screening identified 30 cases (sensitivity, 78.9%; 95% CI, 62.7 to 70.4). There were 9 false positives for T21 in the cell-free DNA testing group (false-positive rate: 0.06%; 95% CI, 0.03 to 0.11). There were 854 false positives for T21 on standard screening (false-positive rate, 5.4%; 95% CI, 5.1 to 5.8). The positive predictive value (PPV) for the entire sample (N=15,841) was 80.9% (95% CI, 66.7 to 90.9) with cell-free DNA testing and 3.4% (95% CI, 2.3 to 4.8) with standard screening.

Among the 488 (3%) of women excluded from the primary analysis due to lack of results on cell-free DNA testing (“no call” group), there were 13 aneuploidies, including 3 cases of T21, 1 case of T18, and 2 cases of T13. The prevalence of aneuploidy in the “no call” group was higher than in the sample as a whole (1/38 [2.7%] and 1/236 [0.4%], respectively). Standard screening identified all of these cases of T21 in the cell-free DNA “no call” group. If these cases were included in the calculation of sensitivity and specificity for detecting T21, the sensitivity of cell-free DNA would be 38 of 41 (92%) and of standard screening would be 33 of 41 (80.5%).

As previously stated, the authors conducted subanalyses of low-risk women. When low risk was defined as age younger than 35 years (n=11,994), cell-free DNA testing identified all 19 cases of T21, with 6 false positives (PPV=76.0%; 95% CI, 54.9 to 90.6). When low risk was defined as a risk less than 1 in 270 on standard screening (n=14,957), cell-free DNA identified all 8 cases of T21, with 6 false positives (PPV=50%; 95% CI, 24.7 to 75.3)

Section Summary
There are fewer data on the diagnostic accuracy of cell-free DNA testing of women with average-risk singleton pregnancies. The available prospective studies in general population samples (which include both high- and average-risk women), including the large Norton et al 2015 study, have found high sensitivity and specificity rates, similar to that seen in high-risk women. In the Norton study, although PPV was lower in the subsample of low-risk women than in the general population, PPV of cell-free DNA testing was much higher than standard screening.

Twin and Multiple Pregnancies
Detection of T21 in twin pregnancies was systematically evaluated in only 1 study, published in 2012 by Canick et al; the study used the Sequenom test.21 All 7 cases of twin pregnancies with Down syndrome were correctly classified. Five of these were discordant, where 1 twin had T21 aneuploidy and the other did not; 2 were concordant where both twins had T21 aneuploidy. There is a lack of data on detection of T18, T13, and sex chromosome aneuploidies in twin and multiple pregnancies.

Section Summary
For women with multiple pregnancies, there is insufficient evidence to draw conclusions about the diagnostic accuracy of sequencing-based tests for detecting fetal aneuploidies.

What Is the Clinical Utility of the Available Maternal Plasma DNA Sequencing–Based Tests
for Aneuploidy?
The 2013 and 2014 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:
    ˇ 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.
    ˇ 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.
    ˇ 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 the one 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 that 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:
    ˇ High-risk women: Assuming 75% uptake after a positive screen, the maximum cases detectable in the hypothetical population of 100,000 pregnancies is 127 T18 cases and 45 T13 cases. Standard noninvasive screening would identify 123 of the 127 T18 cases and sequencing-based screening would identify 121 of 127 cases. In addition, standard noninvasive screening would identify 37 of 45 T13 cases and sequencing-based screening would identify 39 of 45 T13 cases.
    ˇ Low-risk women: Assuming 50% uptake after a positive screen, the maximum cases detectable in the hypothetical population of 100,000 pregnancies is 20 T18 cases and 6 T13 cases. Each initial screening test would identify 19 of the 20 T18 cases and 5 of the 6 T13 cases.

Results of the modeling suggest that sequencing-based tests detect a similar number of T13 and T18 cases and miss fewer cases compared with 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.

In addition to the TEC Assessments, several other published articles presented decision models in published articles and these are described next.

Garfield and Armstrong published a study in 2012 in modeling use of the Illumina test.22 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, detection of T21 increased from 148 with standard testing to 170 with VerifiŽ testing and detection of T18 increased from 44 to 45. 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.

In 2012, Palomaki et al 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.7 The model included cases positive for T21 or T18 (but not T13 due to its lower prevalence). As in the 2012 TEC Assessment, they assumed 4.25 million births in the United States 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 with the highest performing standard screening test, the addition of sequencing-based screening would increase the Down syndrome detection rate from 4450 to 4702 and decrease the number of miscarriages associated with invasive testing from 350 to 34.

In 2013, Ohno and Caughey published a decision model comparing use of sequencing-based tests in high-risk women with confirmatory testing (ie, as a screening test) and without confirmatory testing (ie, as a diagnostic test).23 Results of the model concluded that using sequencing-based tests with a confirmatory test results in fewer losses of normal pregnancies compared with sequencing-based tests used without a confirmatory test. The model made their estimates using the total population of 520,000 high-risk women presenting for first-trimester care each year in the United States. Sequencing-based tests used with confirmatory testing resulted in 1441 elective terminations (all with Down syndrome). Without confirmatory testing, sequencing-based tests resulted in 3873 elective terminations, 1449 with Down syndrome and 2424 without Down syndrome. There were 29 procedure-related pregnancies losses when confirmatory tests were used. The decision model did not address T18 or T13.

It is important to note that all of the previously discussed 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.

Section Summary
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.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed in Table 2.

Table 2. Summary of Key Trials
Trial Name
Planned Enrollment
Completion Date
NCT01545674aPrenatal Non-invasive Aneuploidy Test Utilizing SNPs Trial (PreNATUS)
Dec 2015
NCT01597063aA Clinical Study to Evaluate the Relative Clinical Specificity Performance of the SEQureDx Trisomy Test in Pregnant Women at Low Risk for Fetal Chromosomal Aneuploidy
Dec 2015
NCT01925742PEGASUS: PErsonalized Genomics for Prenatal Aneuploidy Screening Using Maternal Blood
Jan 2017
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence
Published studies on commercially available tests and meta-analyses of these studies have consistently demonstrated very high sensitivity and specificity for detecting Down syndrome (trisomy 21 [T21]) in singleton pregnancies. Most of the studies included only women at high risk of T21 but several studies, including one with a large sample size, have reported similar levels of diagnostic accuracy in average-risk women. Compared with standard serum screening, both the sensitivity and specificity of cell-free DNA screening is considerably higher. As a result, screening with cell-free DNA will result in fewer missed cases of Down syndrome, fewer invasive procedures, and fewer cases of pregnancy loss following invasive procedures. There is insufficient evidence that noninvasive prenatal testing using cell-free fetal DNA is accurate for detecting fetal aneuploidy in twin and multiple pregnancies.

There is less published evidence on the diagnostic performance of sequencing-based tests for detecting trisomies T18, T13, and sex chromosome anomalies, and most of the available studies were conducted in high-risk pregnancies. Meta-analyses of available data suggest high sensitivities and specificities, but the small number of cases, especially for T13, makes definitive conclusions difficult. The findings of a decision analysis study included in the 2014 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 T21 screening. Due to the low survival rate, the clinical benefit of identifying trisomy 18 and 13 are unclear. The clinical utility of early sex chromosome aneuploidy detection is also unclear.

Supplemental Information

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 3 physician specialty societies and 4 academic medical centers while this policy was under review in 2012. There was consensus that sequencing-based tests to determine T21 from maternal plasma DNA may be considered medically necessary in women with high-risk singleton pregnancies undergoing screening for T21. Input was mixed on whether sequencing-based tests to determine T21 from maternal plasma DNA may be considered medically necessary in women with average-risk singleton pregnancies. An American College of Obstetricians and Gynecologists (ACOG) Genetics Committee Opinion, included as part of the specialty society’s input, does not recommend the new tests at this time for women with singleton pregnancies who are not at high risk of aneuploidy. There was consensus that sequencing-based tests to determine T21 from maternal plasma DNA are investigational for women with multiple pregnancies. In terms of an appropriate protocol for using sequencing-based testing, there was consensus that testing should not be used as a single-screening test without confirmation of results by karyotyping. There was mixed input on use of the test as a replacement for standard screening tests with karyotyping confirmation and use as a secondary screen in women with screen positive on standard screening tests with karyotyping confirmation. Among the 5 reviewers who responded to the following questions (which did not include ACOG), there was consensus that the modeling approach is sufficient to determine the clinical utility of the new tests and near-consensus there is a not a need for clinical trials comparing a screening protocol using the new tests to a screening protocol using standard serum screening before initiation of clinical use of the tests.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine
On June 25, 2015, ACOG and the Society for Maternal-Fetal Medicine released an updated committee opinion on noninvasive testing for fetal aneuploidy.24 (This document replaces the November 2012 ACOG committee opinion which recommended that maternal plasma DNA testing be offered only to women at increased risk of fetal aneuploidy25). The complete list of recommendations in the 2015 committee opinion follows:
    ˇ “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.
    ˇ 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.
    ˇ 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.
    ˇ The cell-free DNA test will screen for only the common trisomies and, if requested, sex chromosome composition.
    ˇ 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.
    ˇ Parallel or simultaneous testing with multiple screening methodologies for aneuploidy is not cost-effective and should not be performed.
    ˇ Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone.
    ˇ 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.
    ˇ Routine cell-free DNA screening for microdeletion syndromes should not be performed.
    ˇ Cell-free DNA screening is not recommended for women with multiple gestations.
    ˇ If a fetal structural anomaly is identified on ultrasound examination, diagnostic testing should be offered rather than cell-free DNA screening.
    ˇ Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy.
    ˇ 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.
    ˇ Patients may decline all screening or diagnostic testing for aneuploidy.”

National Society of Genetic Counselors
In 2013, the National Society of Genetic Counselors (NSGC) published a position statement regarding noninvasive prenatal screening of cell-free DNA in maternal plasma.26 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 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.27 Limitations identified by the organization 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.

International Society for Prenatal Diagnosis
In 2013, the International Society for Prenatal Diagnosis published a position statement regarding prenatal diagnosis of chromosomal abnormalities.28 The statement included the following discussion of maternal cell-free DNA screening:

    Although rapid progress has been made in the development and validation of this technology, demonstration that in actual clinical practice, the testing is sufficiently accurate, has low failure rates, and can be provided in a timely fashion, has not been provided. Therefore, at the present time, the following caveats need to be considered….

    Reliable noninvasive maternal cfDNA (cell-free) aneuploidy screening methods have only been reported for trisomies 21 and 18….

    There are insufficient data available to judge whether any specific cfDNA screening method is most effective.

    The tests should not be considered to be fully diagnostic and therefore are not a replacement for amniocentesis and CVS….

    Analytic validity trials have been mostly focused on patients who are at high risk on the basis of maternal age or other screening tests. Efficacy in low-risk populations has not yet been fully demonstrated….

U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (USPSTF) does not currently address screening for Down syndrome. This topic had been addressed in the 1990s, but the topic is no longer listed on the USPSTF website.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.]

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.


Noninvasive Prenatal Screening for Fetal Aneuploidies Using Cell-Free Fetal DNA
Noninvasive Prenatal Testing for Fetal Aneuploidies Using Cell-Free Fetal DNA
Noninvasive Prenatal Testing for Trisomy 21 Using Cell-Free Fetal DNA
Sequencing-Based Tests to Determine Trisomy 21 from Maternal Plasma DNA
Maternal Plasma DNA Test for Fetal Aneuploidy
MaterniT21 Plus
Harmony Prenatal Test
Sequenom's MaterniT21 Plus
Ariosa Diagnostic's Harmony Prenatal Test
Aneuploidy, Maternal Plasma DNA Test
DNA Test for Fetal Aneuploidy Using Maternal Plasma
Fetal Aneuploidy, Maternal Plasma DNA Test for
Cell-Free Fetal DNA Test for Aneuploidy
Trisomy 13, Maternal Plasma DNA Test for
Trisomy 18, Maternal Plasma DNA Test for
Trisomy 21, Maternal Plasma DNA Test for
Down Syndrome, Maternal Plasma DNA Test for
Edwards Syndrome, Maternal Plasma DNA Test for
Patau Syndrome, Maternal Plasma DNA Test for
Verinata Health's Verify Prenatal Test
Illumina Verifi Prenatal Test
Verifi Prenatal Test
Natera Panorama Prenatal Test
Panorama™ Prenatal Test
Integrated Genetics InformaSeq Prenatal Test
LabCorp Specialty Testing Group's InformaSeq Prenatal Test
InformaSeq Prenatal Test
Quest Diagnostics QNatal Advanced Tests
QNatal Advanced Tests

1. 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

2. 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

3. 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).

4. 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.

5. Food and Drug Adminstration (FDA). Ultra High Throughput Sequencing for Clinical Diagnostic Applications - Approaches to Assess Analytical Validity, June 23, 2011 (Archived Content). http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm255327.htm. Accessed April, 2014.

6. 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. PMID 24513694

7. 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

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 2011;13(11):913-920. PMID 22005709

9. 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

10. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. May 2012;119(5):890-901. PMID 22362253

11. 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

12. 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. PMID

13. 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

14. 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

15. 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

16. 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

17. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. Feb 27 2014;370(9):799-808. PMID 24571752

18. 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.

19. Gil MM, Quezada MS, Bregant B, et al. Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. Ultrasound Obstet Gynecol. Jul 2013;42(1):34-40. PMID 23744609

20. 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

21. 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

22. 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.

23. Ohno M, Caughey A. The role of noninvasive prenatal testing as a diagnostic versus a screening tool--a cost-effectiveness analysis. Prenat Diagn. Jul 2013;33(7):630-635. PMID 23674316

24. Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. Obstet Gynecol. Jun 25 2015. PMID 26114726

25. American College of Obstetricians and Gynecologists (ACOG). Commitee Opinion: Noninvasive Prenatal Testing for Fetal Aneuploidy. 2012; http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/Noninvasive_Prenatal_Testing_for_Fetal_Aneuploidy. Accessed April, 2014.

26. Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. J Genet Couns. Jun 2013;22(3):291-295. PMID 23334531

27. 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

28. 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.

(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)



ICD-9 Diagnosis

ICD-9 Procedure

* CPT only copyright 2015 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.


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