| Coverage Policy Manual | |
| Policy #: | 2004016 |
| Category: | Radiology |
| Initiated: | May 2004 |
| Last Review: | April 2023 |
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| Ultrasound in Maternity Care: 1st Trimester Detection of Down Syndrome using Fetal US Assessment of Nuchal Translucency & Maternal Serum Assessment | |
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| Description: |
Over the years many types of biologic markers have been investigated for utility in detecting Down syndrome fetuses. Fetal nuchal translucency refers to the ultrasound detection of subcutaneous edema in the fetal neck, and is measured as the maximal thickness of the sonolucent zone between the inner aspect of the fetal skin and the outer aspect of the soft tissue overlying the cervical spine or the occipital bone. In the early 1990s, screening studies of pregnant women reported an association between increased nuchal translucency in the first trimester of pregnancy (10–13 weeks of gestation) and chromosomal defects, most commonly Down syndrome, but also trisomy 18 and 13.
Recently, two studies have been published that evaluate the use of nuchal translucency in combination with other maternal serum markers to detect Down syndrome. The methodology and analytic methods of the studies reflect an important maturation, in that nuchal translucency interpretation is standardized and incorporated into appropriate statistical models in combination with other maternal serum markers that are also known to be associated with Down syndrome in the first trimester. First-trimester screening, if accurate, can provide important information to the mother several weeks before it would be available with traditional second-trimester screening.
To understand the potential role of this technique, the following discussion reviews established screening methods. Definitive diagnosis of Down syndrome and other chromosomal abnormalities requires amniocentesis or chorionic villus sampling (CVS), both of which are invasive procedures that carry a risk of miscarriage estimated at 0.5% to 1%. Because of this risk, before biochemical screening existed, diagnosis was generally only offered to women 35 years or older, for whom the risk of the procedure approximated the risk of Down syndrome. However, the majority of Down syndrome babies are born from mothers younger than 35 years, even though the mothers are at lower individual risk. This situation created interest in developing less-invasive screening programs based on assessment of serum markers that have shown associations with Down syndrome. In the late 1980s, biochemical screening at 16 weeks' gestation was developed and began to be offered to all pregnant women. Biochemical screening consists of maternal serum measurements of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol (i.e., triple screen); using this screening method, approximately 60% of Down syndrome pregnancies can be identified at a 5% false-positive rate. This false-positive rate refers to the proportion of all tests administered that are falsely positive at the cutoff that produces that particular value of sensitivity. Among women who test positive, only about 2% actually have a Down syndrome fetus. A fourth biochemical marker, inhibin-A has also been included in biochemical screening (i.e., quadruple screen) that may boost detection to 75% at a false-positive rate of 5%.
The nuchal translucency measurement is an ultrasound imaging procedure performed in the first trimester of pregnancy to detect various chromosomal abnormalities in the fetus. In this procedure, ultrasound is used to identify and measure fluid collections between the tissue covering the spine and the skin that covers it. This imaging procedure takes advantage of the hyperechoic quality of this ultrasonographic anatomical feature. The calculation of chromosomal abnormality risk utilizes in the equation the measurements of maternal age; gestational age; and the deviation of the thickness of the nuchal translucency from the norm as compared to the crown-rump length of the fetus.
Regulatory Status
Fetal ultrasound uses available instrumentation and as a medical procedure is not subject to regulation by the US Food and Drug Administration (FDA).
Coding
Two new codes, 76813 and 76814, were added to report nuchal translucency measurement, an ultrasound procedure performed for the detection of chromosomal abnormalities such as Down syndrome. This procedure can be performed using either a transabdominal or transvaginal approach. Code 76813 is reported when the fetal nuchal translucency measurement is performed in a single or the first gestation. Add-on code 76814 was established to report each additional gestation. An instructional parenthetical note was added after code 76814 directing users to report code 76814 in conjunction with code 76813. A cross-reference was added following existing codes 76801, 76802, and 76815 directing users to report codes 76813 and 76814 for fetal nuchal translucency measurement.
Effective in 2013, there are multianalyte assays with algorithmic analyses (MAAA) codes for some combinations of these maternal serum markers.
Prior to the creation of the specific MAAA codes for the triple, quad and penta screens, laboratories were reporting the codes for the component tests. Now that there are specific MAAA codes for these screens, the MAAA codes should be reported. If a component test (e.g., PAPP-A, hCG, AFP, etc.) is performed independently for a quantitative result without an algorithmic analysis or risk score, the CPT code for the individual test (84163, 84702, 82105, respectively) would be reported.
The 5 MAAA codes are:
81508 Fetal congenital abnormalities, biochemical assays of two proteins (PAPP-A, hCG [any form]), utilizing maternal serum, algorithm reported as a risk score
(Do not report 81508 in conjunction with 84163, 84702)
81509 Fetal congenital abnormalities, biochemical assays of three proteins (PAPP-A, hCG [any form], DIA), utilizing maternal serum, algorithm reported as a risk score
(Do not report 81509 in conjunction with 84163, 84702, 86336)
81510 Fetal congenital abnormalities, biochemical assays of three analytes (AFP, uE3, hCG [any form]) utilizing maternal serum, algorithm reported as a risk score (may include additional results from previous biochemical testing)
(Do not report 81510 in conjunction with 82105, 82677, 84702)
81511 Fetal congenital abnormalities, biochemical assays of four analytes (AFP, uE3, hCG [any form], DIA) utilizing maternal serum, algorithm reported as a risk score (may include additional results from previous biochemical testing)
(Do not report 81511 in conjunction with 82105, 82677, 84702, 86336)
81512 Fetal congenital abnormalities, biochemical assays of five analytes (AFP, uE3, total hCG, hyperglycosylated hCG, DIA) utilizing maternal serum, algorithm reported as a risk score
(Do not report 81512 in conjunction with 82105, 82677, 84702, 86336)
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Policy/ Coverage: |
Effective April 2011
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
First-trimester screening for detection of Down syndrome, which consists of a calculation of risk based on maternal age, free or total human chorionic gonadotropin (total ß-hCG), pregnancy-associated plasma protein A (PAPP-A), and ultrasonic measurement of fetal nuchal translucency, may meet primary coverage criteria for effectiveness for women who are adequately counseled and desire information on the risk of having a child with Down syndrome.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of nuchal translucency, with or without PAPP-A and free-beta hCG, outside of the first trimester, or in any circumstance other than that noted above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, the use of nuchal translucency, with or without PAPP-A and free-beta hCG, outside of the first trimester, or in any circumstance other than that noted above, is considered investigational. Investigational services are member benefit contract exclusions.
The use of fetal nasal bone assessment for first-trimester screening for detection of Down syndrome does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, the use of fetal nasal bone assessment for first-trimester screening for detection of Down syndrome is considered investigational. Investigational services are member benefit contract exclusions.
Effective prior to April 2011
First-trimester screening for detection of Down syndrome, which consists of a calculation of risk based on maternal age, free or total human chorionic gonadotropin (total β-hCG), pregnancy-associated plasma protein A (PAPP-A), and ultrasonic measurement of fetal nuchal translucency, may meet primary coverage criteria for effectiveness and be covered for women who are adequately counseled and desire information on the risk of having a child with Down syndrome.
When coverage criteria is met ultrasound testing for the purpose of measuring nuchal translucency meets primary coverage criteria for effectiveness and is covered only when performed by a sonographer certified in this technique by the American Institute of Ultrasound in Medicine (AIUM) or the Fetal Medicine Foundation.
The use of nuchal translucency, with or without PAPP-A and free-beta hCG, outside of the first trimester, or in any circumstance other than that noted above, is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, the use of nuchal translucency, with or without PAPP-A and free-beta hCG, outside of the first trimester, or in any circumstance other than that noted above, is considered investigational and is not covered. Investigational services are a member benefit contract exclusion.
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| Rationale: |
The standard of care for screening for Down syndrome consists of offering second trimester biochemical screening to all women under the age of 35, and either biochemical screening or amniocentesis/chorionic villus sampling (CVS) to those over the age of 35. It is important to realize that the evaluation of first-trimester screening does not involve examining the role of nuchal translucency alone, but the combination of maternal serum and nuchal translucency assessment, including the computer algorithm to calculate risk of Down syndrome. In clinical studies, the laboratory and imaging components of the screening are performed in a coordinated fashion. This whole process results in a set of predictions of Down syndrome, which can be summarized by ROC analysis or sensitivity and specificity estimates. Although multiple cut-off points are possible, a standard method of presenting results is to report the sensitivity at the cutoff that produces a 5% false-positive rate. In actual practice, however, patients are not just informed of a “positive” or “negative” result, but are given a numerical estimate (“1 out of XX”) of the probability of Down syndrome. These probability estimates may help aid further decision making by the patient. The currently used triple screen is analyzed in exactly the same way as the first-trimester screen, so the 2 methods produce directly comparable predictions.
Of concern have been the possible variability of ultrasonographic interpretation and the generalizability of results of research studies. Ultrasonography is operator dependent, which may introduce variability in results. The Fetal Medicine Foundation, which has published extensively in the field of nuchal translucency measurement, emphasizes the importance of adequate training of sonographers and ongoing quality assurance. The validity of this concern has been demonstrated in a recent report by Haddow et al., in which nuchal translucency was performed in 16 centers across the United States. To address these issues, the Fetal Medicine Foundation has developed a training program with a process of accreditation and ongoing quality control. In the 2 recent studies that will be reviewed in this report, ultrasounds were performed by several sonographers at different sites. In the study by Wapner et al., there were 40 sonographers at 12 participating sites. In the study by Wald et al., there were 260 sonographers at 25 participating sites. Thus, the results of these studies do not merely reflect the capability of a single sonographer or single site with great expertise, but do reflect the results of sonographers that have undergone specific training and certification. This training and certification, along with an appropriate reference database of patients and use of statistical methodology, are necessary to produce optimal diagnostic results. The study by Wapner et al. states “… a learning period was required, with measurements becoming more consistent over time. This required stringent training, formalized evaluation... of ... competence, and continuing external quality control.”
Trial design issues include the population of patients studied (i.e., high risk or average risk) and the quality follow-up to avoid verification bias. Verification bias refers to a problem in which the outcome status (Down syndrome or normal) is not assessed or is not available in certain patients. In the context of Down syndrome screening, spontaneous abortion is more likely in fetuses with chromosomal anomalies. Fetuses that miscarry may be more likely to be Down syndrome fetuses, and may be missed among those who have negative screening tests. Therefore, unless karyotyping is performed in all cases of spontaneous abortion or stillbirth, it is likely that a certain percentage of Down syndrome fetuses will go undetected. Therefore, to avoid verification bias, it is important to have as complete a follow-up as possible of all pregnancy outcomes with karyotypic analysis on stillbirths and live births with dysmorphic features and phenotypic assessment of other live births. However, any bias in comparison between first- and second-trimester screenings is likely to be small, most likely on the order of about 3% difference in absolute sensitivity. The Serum, Urine, and Ultrasound Screening Study (SURUSS) study (Wald et al.) enrolled over 47,000 women, of whom 101 had fetuses with Down syndrome. This study evaluated several tests all in parallel, including first-trimester testing with nuchal translucency and maternal markers, the triple test, second-semester quadruple test, and a combined first- and second-trimester test (both with and without nuchal translucency). There were very high rates of verification, and adjustments were applied to account for miscarriages. Calculation of risk for all tests was done with a similar analytic methodology. There is no abnormal cutoff threshold for any measurement of nuchal translucency or maternal serum analyte, as all measurements are entered into the regression model as continuous variables. In a direct comparison of the first trimester test to the triple test, at a threshold of 85% detection, the first-trimester test had a false-positive rate of 6.1%, and the triple test had a false-positive rate of 9.3%. The lower false-positive rate at the same sensitivity means that the first-trimester test has superior discriminative capacity. Setting the false-positive rate at 5% results in a sensitivity of 83%, which is superior to what is historically expected of the triple test. The study also evaluated nuchal translucency measurement alone. Its performance was considerably worse than either first-trimester testing or the triple test, with a false-positive rate of 20% at a diagnostic sensitivity of 85%.
The BUN study (Wapner et al.), was also published in 2003, and evaluated first-trimester screening using the nuchal translucency and the same maternal markers (human chorionic gonadatropin and pregnancy-associated plasma protein A) as the SURUSS study. Approximately 8,500 patients were enrolled, and 61 cases of Down syndrome were identified. Using a screening threshold of 1/270, 85% of cases were detected with a false-positive rate of 9.4%. If the threshold were changed to produce a false-positive rate of 5%, the detection rate was 78.7%. Taking into account possible biases due to miscarriages, the authors calculated that second-trimester screening would have to be 75% sensitive to be equivalent to the 78.7% sensitivity they found for first-trimester screening. Other screening tests such as the triple test or other combined tests were not evaluated in this study.
A further follow-up of the BUN study was reported by Platt and colleagues. This analysis focused on sequential pathways of testing after first-trimester screening for Down syndrome using fetal nuchal translucency. All patients were offered the option of additional second-trimester screening, either to further evaluate a positive screening result in the first trimester or to offer additional screening to those whose first-trimester test was negative. The status of all fetuses was reported. A total of 4,145 women with a negative first-trimester screen underwent additional second-trimester screening. In this group there were a total of 7 infants with Down syndrome; the second trimester screen identified 6 of the 7 (86%), but with a false positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 Down syndrome fetuses were identified, but with a false positive rate of 38.7%. The authors concluded that a sequential screening program that provided patients with the results of first-trimester screening with the option of an early invasive test (i.e., amniocentesis or chorionic villus sampling) or additional screening in the second trimester can identify 98% of fetuses with Down syndrome. This approach would result in 17% of patients inaccurately considered at high risk.
These 2 large, multicenter studies show similar or greater estimates of sensitivity of first-trimester screening when compared either directly to second-trimester screening or historical estimates of second-trimester screening. The SURUSS study demonstrates that nuchal translucency assessment alone is inferior to either second- or first-trimester combined screening.
Results for the FASTER (First and Second Trimester Evaluation of Risk) trial, sponsored by the National Institute of Child Health and Human Development (NIHCHD) were published in November 2005. Malone and associates reported that first-trimester screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin) at 11 weeks gestation is better than second trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol and inhibin A). Rates of detection of Down’s syndrome were 87% for first-trimester testing done at 11 weeks but falling to 82% at thirteen weeks. Detection rate for second trimester screening was 81%, all with a 5% false positive rate.
Detection rates were higher (95%) with stepwise sequential screening, 88% with serum integrated screening and 96% with fully integrated screening when the first-trimester screening was performed at 11 weeks.
The American College of Obstetrics and Gynecology published a Practice Bulletin, Screening for Fetal Chromosomal Abnormalities, in January 2007. Recommendations based on good and consistent scientific evidence include:
2008 Update
The new code for measurement of free beta chain human chorionic gonadotropin was introduced into the AMA Current Procedural Terminology ® in 2008 (CPT 84704). This test is a biochemical marker used during the first trimester in combination with the PAPP-A test and the nuchal translucency measurement to predict the risk of Down syndrome and trisomy 18/13. This test is patented and offered only by one laboratory.
2011 Update
This policy update primarily deals with fetal nasal bone assessment for screening for detection of Down Syndrome.
A systematic review by Rosen and colleagues for the U.S.-based Maternal Fetal Medicine Foundation Nuchal Translucency Oversight Committee identified 10 studies in a 2006 MEDLINE search on fetal nasal bone performance (Rosen, 2007). A total of 35,312 women underwent first-trimester ultrasound assessment of fetal nasal bone. The fetal nasal bone was successfully imaged in 33,314 (94.3%) of cases and could not be imaged in 5.7% of cases. There were 479 Down syndrome fetuses, a prevalence of 13.6 in 1,000. The authors note that this is 10 times the first-trimester incidence in the U.S., suggesting a high-risk population had been screened. The fetal nasal bone was absent in 310 of 479 (65%) Down syndrome cases and in 274 of 34,048 (0.8%) chromosomally normal cases.
One of the included studies, a subanalysis of the FASTER study, discussed above, involved a general population sample and had much lower rates of successful imaging than other studies (Malone, 2004). Assessment of fetal nasal bone was added to the FASTER protocol during the last 7 months, but did not occur in all centers. A total of 6,324 women underwent fetal nasal bone sonography and pregnancy outcome data were available for 6228 (98.5%) of them. Sonographers failed to obtain an adequate view in 1,523 patients (24%). Among the 4,801 cases with adequate images of the fetal profile, the nasal bones were described as being absent in 22 (0.5%) of them. There were 11 identified cases of Down syndrome.
Fetal nasal bone assessment did not identify any of these cases as potentially high risk. In 9 of the 11 cases (92%), the fetal nasal bones were judged to be present, and in 2 cases, were unable to determined. There were also 2 cases of trisomy 18; nasal bones were present in one and absent in the other. The FASTER investigators concluded that first-trimester fetal nasal bone sonography does not seem to have a role in general population screening for Down syndrome. Other researchers have commented on the lower rate of successful fetal nasal bone assessment in the FASTER analysis. The Rosen review article (Rosen, 2007) noted that, although the sonographers were trained and experienced in nuchal translucency measurement, they were new to fetal nasal bone assessment. Another review article by Sonek and colleagues states that the likely explanation for the FASTER findings is that their techniques were different from those used by others (Sonek,2006).
One study was identified that directly compared the performance of fetal nasal bone assessment in unselected and selected populations (Prefumo, 2006). This prospective study included a total of 7,672 pregnant women, 7116 of whom were at average risk and 510 at increased risk (more than 1 in 300) of Down syndrome based on age, family history, or previous pregnancy history. It was not possible to adequately assess the fetal nasal bones in 712 of 7,116 (10%) in a general population sample, and in 42 of 510 (8.2%) in a high-risk sample. A total of 35 cases of Down syndrome were identified, 23 in the selected group and 12 in the unselected group. Two Down syndrome cases in the selected group were excluded because there was not a satisfactory ultrasound examination. In the remaining cases, absent fetal nasal bones identified 10 of 21 (47.6%) Down syndrome cases in the selected population and 2 of 12 (16.7%) in the unselected group. An analysis including the 2 missing cases found that fetal nasal bone assessment was able to correctly identify 10 of 23 or 43.5% of Down syndrome cases. A logistic regression model including fetal nasal bone findings, as well as nuchal translucency and demographic factors, absence of fetal nasal bone was found to be an independent predictor of trisomy 21 in the selected pregnancies group, but not in the unselected pregnancies group.
Several studies were identified that evaluated the diagnostic accuracy of first-trimester screening programs that included fetal nasal bone measurements as part of a comprehensive screening program. None of these was multicenter and none was conducted in the U.S.
Cicero and colleagues conducted a single-center prospective screening study in the UK (Cicero, 2006). Down syndrome screening including fetal nasal bone assessment was conducted in 21,074 singleton pregnancies at 11 to 13 weeks’ gestation. Data from 20,418 (97%) women were available for analysis. Chromosomal abnormalities were detected in 253 of the pregnancies; this included 140 cases of Down syndrome. An adequate view of the fetal profile could not be obtained in 243 (1.2%) of cases. Of the 20,175 cases in which the fetal profile could be obtained (i.e., “successful” examination), the nasal bone was recorded as absent in 238 (1.2%) of cases and present in 19,937 (97.6%). Combined screening with nuchal translucency assessment and maternal serum markers achieved a detection rate of 90% at a fixed false-positive rate of 5%. With the detection rate fixed at 90%, the inclusion of nasal bone measurements using either screening strategy decreased the false-positive rate to 2.5%. In another analysis at a fixed false-positive rate of 5%, the inclusion of fetal nasal bone assessment of all women in the sample increased the detection rate to 93.6% at the 5% false-positive rate. The same increase in the detection rate, to 93.6%, was obtained when fetal nasal bone assessment was included only for women of intermediate risk (one in 51 to one in 1,000).
In a prospective study by Has and colleagues from Turkey, 2,080 women with singleton pregnancies underwent fetal nasal bone ultrasound by trained staff as part of first-trimester screening at 11 to 14 weeks’ gestation (Has, 2008). Data were available for 1,926 (92.6%) of fetuses. The investigators then excluded 110 cases without known chromosomal abnormalities in which there was fetal or neonatal death, pregnancy termination, or survival with malformations. Among the remaining 1,816 pregnancies, the fetal nasal bone could not be evaluated in 9 (0.5%) of the women. Fetal nasal bone was judged to be absent in 10 (0.6%) cases and present in 1,791 (99.4%) of cases. It was absent in 3 of 9 (33.3%) fetuses known to have Down syndrome and 7 of 1,792 (0.4%) of chromosomally normal fetuses. The detection rate of first-trimester screening (nuchal translucency and maternal serum markers) was 8 of 9 (88.9%) affected fetuses with a false-positive rate of 3.6%, using a risk cut-off of one in 300. Incorporating the fetal nasal bone assessment did not change the detection rate, but decreased the false-positive rate from 0.6% to 3.0%.
A study conducted in Hong Kong was a retrospective analysis of 10,767 women who had been screened in a comprehensive first-trimester screening program (Sahota, 2010). The analysis compared several approaches to screening. Among the 10,854 fetuses with a known outcome, 32 had Down syndrome. In a screening approach that combined nuchal translucency assessment and maternal serum markers in this group, 27 (94%) of the pregnancies would have been classified as high risk, 4 as low risk, and 1 as intermediate risk. The protocol included fetal nasal bone assessment of intermediate-risk pregnancies, with reclassification as high risk if the fetal nasal bone was absent. The one case classified as intermediate risk had an absent fetal nasal bone. In this study, too few cases were classified as intermediate risk to determine whether fetal nasal bone assessment in a contingent screening approach improves screening accuracy.
As with nuchal translucency measurement, there are possible issues around variability of fetal nasal bone interpretation and the need for adequate training and quality control. The review article by Rosen and colleagues states that mastering imaging of the nasal bone appears to be more difficult than mastering nuchal translucency measurement (Rosen, 2007). The Committee recommends that sonographers undergo training, gain hands-on experience, and submit images for external review before starting clinical acquisition, and they further recommend ongoing monitoring of nasal bone images locally by an experienced physician. The Fetal Medicine Foundation in the UK has an Internet-based certificate of competency in fetal nasal bone assessment; their website does not state how long this program has been available. It appears that techniques for evaluating fetal nasal bone images continue to be refined. A 2009 article by McLennan and colleagues in New Zealand describe the development of a method of image scoring (McLennan, 2009). In an evaluation of 400 images, they found that, using the new image evaluation approach, 84% of images were judged similarly by 3 raters on 2 separate occasions and in 94% of cases 5 of 6 ratings had the same conclusions.
Another issue is generalizability of nasal bone assessment to general clinical practice. The article by Rosen and colleagues for the Fetal Medicine Foundation Nuchal Translucency Oversight Committee reports that fetal nasal bone assessment studies have come primarily from a few specialized centers. Information on the performance of fetal nasal bone assessment in other settings is lacking (Schmidt, 2008). Moreover, possible differences in findings using different ultrasound techniques or equipment have not been adequately explored. The Oversight Committee recommends further evaluation of nasal bone assessment in low-risk populations, and additional availability of adequately trained centers before nasal bone assessment is introduced into general practice. They also suggest considering a contingent screening strategy. The approach they suggest is similar to that used in the Sahota et al. study (Sahota, 2010) from Hong Kong, discussed above, in which fetal nasal bone assessment is used only in cases that have a borderline risk determination by screening with nuchal translucency and maternal serum markers. If a contingency model were used, patients could be referred to centers with developed expertise, although the authors note that this may not be feasible or practical in all areas of the U.S.
Summary
Studies have found a high rate of successful imaging of the fetal nasal bone and an association between absent nasal bone and the presence of Down syndrome in high-risk populations. However, there is insufficient evidence on the performance of fetal nasal bone assessment in average-risk populations. Of particular concern is the low performance of fetal nasal bone assessment in a subsample of the FASTER study conducted in a general population sample. Two studies conducted outside of the U.S. have found that, when added to a first-trimester screening program evaluating maternal serum markers and nuchal translucency, fetal nasal bone assessment can result in a modest decrease in the false-positive rate. Several experts in the field are proposing that fetal nasal bone assessment be used as a second stage of screening, to screen women found to be of borderline risk using maternal serum markers and nuchal translucency. Additional studies using this contingent approach are needed before conclusions can be drawn about its utility.
2012 Update
Subsequent studies have confirmed that combined first-trimester screening that includes NT measurement and maternal serum markers is superior to NT measurement alone. Ranta and colleagues (2011), in a retrospective review of data on 76,949 women in Finland, found that combined screening with maternal serum markers and NT is especially preferable in women aged 35 years and younger. Studies continue to investigate the optimal approach to testing that balances the desires to maximize detection, minimize false-positive results, minimize unnecessary testing, and provide information to women as early in their pregnancies as possible.
No medical literature has been idenified that would support a revision of the coverage statement.
2013 Update
A search of the MEDLINE database was conducted through September 2013. There was no new information identified that would prompt a change in the coverage statement.
Two studies were identified that confirm that combined first-trimester screening that includes NT measurement and maternal serum markers is superior to NT measurement alone (Berktold, 2013; Peuhkurinen, 2013). In 2013 Peuhkurinen and colleagues in Finland reported on tests performed prospectively in 35,314 pregnant women (Peuhkurinen, 2013). Ninety-five Down syndrome pregnancies were identified. The detection rate was 64.5% for NT alone and 72.4% for combined screening with NT and maternal serum markers. False-positive rates were 4.4% with NT alone and 4.0% with combined screening.
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2013 study by Torella et al in Italy reported the performance of 2-stage first-trimester combined screening (Torella, 2013). Blood samples were taken at 8 weeks 0 days to 10 weeks 6 days and NT measurement was performed at 12 weeks 0 days to 12 weeks 6 days. The combined screen was considered positive when the risk of Down syndrome was greater than 1 in 250. A total of 73 positive cases were identified among 713 women with singleton pregnancies who were screened. All 73 women underwent invasive testing and 5 cases of trisomy 21 were detected. There was also 1 false negative case. Using this approach, the Down syndrome detection rate was 83% and the false positive rate was 3.2%.
A 2014 prospective study conducted by Hsiao et al in Taiwan included 20,586 women who were screened with maternal serum markers and various ultrasound markers (Hsiao, 2014). The combination of maternal serum markers and NT measurement had a 66.7% detection rate of trisomy 21. The addition of fetal nasal bone measurement increased the detection rate to 88.2%. Further inclusion of more ultrasound markers ie, tricuspid regurgitation and the Doppler velocity waveform of the ductus venosus continued to increase the detection rate.
Techniques for evaluating fetal nasal bone images continue to be refined. A 2014 article reported on the feasibility of assessing fetal nasal bone using the retronasal triangle view (Adiego, 2014). A total of 1977 women pregnant with singletons were scanned using this approach. The retronasal triangle view was successfully obtained for 1970 (99.6%) fetuses. The prevalence of an absent or hypoplastic fetal nasal bone was 12 of 1728 (0.7%) in euploid fetuses and 12 of 17 (70.6%) in fetuses with trisomy 21. The sensitivity and specificity of an absent or hypoplastic fetal nasal bone for detecting trisomy 21 was 70.6% and 99.3%, respectively. Another technique under investigation is use of 3-dimensional ultrasound to measure fetal nasal bone during the first trimester. Nanni et al evaluated 161 women pregnant with singletons with both 2-dimensional and 3-dimensional ultrasound (Nanni, 2014). There was high intraobserver and interobserver agreement using 3-dimensional ultrasound. The agreement between 2-dimensional and 3-dimensional ultrasound was moderate (correlation coefficient=0.77).
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2014 study by Chanprapaph and colleagues in Thailand assessed the presence or absence of fetal nasal bone in 190 fetuses (Changrapaph, 2014). To be included in the study, pregnant women needed to be at increased risk for fetal aneuploidy such as advanced maternal age, previous pregnancy with abnormal chromosome or abnormal sonographic markers or serum tests. An absent nasal bone was identified in 5 of 190 (2.6%) of the fetuses and, as a standalone marker, had a sensitivity of 28.57% and specificity of 99.43% for detecting fetal aneuploidy. In this study, other sonographic markers were measured but no serum testing was conducted. The combination of a positive nuchal translucency and fetal nasal bone test had a sensitivity of 71.43% and specificity of 95.45%.
2017 Update
A literature search conducted using the MEDLINE database through March 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through March 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
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| References: |
Adiego B, Martinez-Ten P, Illescas T et al.(2014) First-trimester assessment of nasal bone using retronasal triangle view: a prospective study. Ultrasound Obstet Gynecol 2014; 43(3):272-6. Berktold L, C VK, Hillemanns P et al.(2013) Analysis of the impact of PAPP-A, free beta-hCG and nuchal translucency thickness on the advanced first trimester screening. Arch Gynecol Obstet 2013; 287(3):413-20. Brameld KJ, Dickinson JE, O’Leary P et al.(2008) First trimester predictors of adverse pregnancy outcomes. Aust N Z J Obstet Gynecol 2008; 48(6):529-35. Canadian Agency for Drugs & Technologies in Health.(2007) Nuchal translucency measurement in first trimester Down Syndrome screening. Issue 100; June 2007. Chanprapaph P, Dulyakasem C, Phattanchindakun B.(2014) Sensitivity of multiple first trimester sonomarkers in fetal aneuploidy detection. J Perinat Med. Sep 13 2014. PMID 25222592 Cicero S, Avgidou K, Rembouskos G et al.(2006) Nasal bone in first-trimester screening for trisomy 21. 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